Download Human mitochondrial transfer RNAs: Role of pathogenic

INVITED REVIEW
ABSTRACT: The human mitochondrial genome encodes 13 proteins. All
are subunits of the respiratory chain complexes involved in energy metabolism. These proteins are translated by a set of 22 mitochondrial transfer
RNAs (tRNAs) that are required for codon reading. Human mitochondrial
tRNA genes are hotspots for pathogenic mutations and have attracted
interest over the last two decades with the rapid discovery of point mutations
associated with a vast array of neuromuscular disorders and diverse clinical
phenotypes. In this review, we use a scoring system to determine the
pathogenicity of the mutations and summarize the current knowledge of
structure–function relationships of these mutant tRNAs. We also provide
readers with an overview of a large variety of mechanisms by which mutations may affect the mitochondrial translation machinery and cause disease.
Muscle Nerve 37: 150 –171, 2008
HUMAN MITOCHONDRIAL TRANSFER RNAs:
ROLE OF PATHOGENIC MUTATION IN DISEASE
FERNANDO SCAGLIA, MD, and LEE-JUN C. WONG, PhD
Department of Molecular and Human Genetics, Baylor College of Medicine,
One Baylor Plaza, Houston, Texas 77030, USA
Accepted 17 September 2007
Normal
mitochondrial function depends on both
the expression of the mitochondrial genome and the
expression of at least 1,300 nuclear genes whose
products are imported into the mitochondria. Human mitochondrial DNA (mtDNA) is a 16,569-kb
circular, double-stranded molecule. It encodes 13 of
more than 80 polypeptide subunits of the mitochondrial respiratory chain complexes and contains 24
additional genes required for mitochondrial protein
biosynthesis. These include two rRNA genes and 22
tRNA genes, one for each of 20 amino acids, and two
each for tRNALeu (UUR and CUN codons) and
tRNASer (UCN and AGY codons).140 All partners of
the mitochondrial protein synthetic machinery such
as aminoacyl-tRNA synthetases, initiation, elongaAvailable for Category 1 CME credit through the AANEM at
www.aanem.org.
Abbreviations: A, adenine; ATP, adenosine triphosphate; C, cytosine; COX,
cytochrome c oxidase; CPEO, chronic progressive external ophthalmoplegia;
DHU, dihydrouridine; G, guanine; mtDNA, mitochondrial deoxyribonucleic
acid; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MERRF, myoclonic epilepsy with ragged-red fibers; NO, nitric
oxide; PEO, progressive external ophthalmoplegia; RC, respiratory chain;
ROS, reactive oxygen species; rRNA, ribosomal ribonucleic acid; SNHL, sensorineural hearing loss; T, thymine; tRNA, transfer ribonucleic acid; U, uracil
Key words: cardiomyopathy; chronic progressive external ophthalmoplegia;
diabetes mellitus; encephalomyopathy; focal segmental glomerulosclerosis;
human mitochondrial tRNA genes; mitochondrial cytopathies; mitochondrial
myopathy; myoclonic epilepsy; pathogenic mutations; ragged-red fibers; retinitis pigmentosa; sensorineural hearing loss; stroke-like episodes
Correspondence to: L. J. C. Wong; e-mail: [email protected]
© 2007 Wiley Periodicals, Inc.
Published online 9 November 2007 in Wiley InterScience (www.interscience.
wiley.com). DOI 10.1002/mus.20917
150
Human Mitochondrial tRNAs
tion and termination factors, ribosomal proteins,
and enzymes involved in maturation and posttranscriptional modification of tRNAs are nuclear encoded. However, the complete set of 22 tRNAs and
two major rRNAs are of mitochondrial origin.
The adaptation of the bacterial ancestors of mitochondria to the new environment of eukaryotic cells
brought the advantage of ATP production via the process of oxidative phosphorylation. However, the presence in mitochondria of an electron transport chain
that continuously reduces oxygen to build up an electrochemical gradient required for ATP synthesis has a
potentially deleterious side effect for these eukaryotic
cells. This side effect consists of the constant generation of reactive oxygen species (ROS). Due to the
continuous function of the electron transport chain,
the minimal electron leakage is sufficient to make mitochondrial O2.- generation the major cellular source
of ROS in most tissues. MtDNA is located in the mitochondrial matrix and its close proximity to the respiratory chain complexes embedded in the inner membrane renders it susceptible to oxidative stress, causing
its high mutation rate (10 –17-fold higher rate of mutations than the nuclear genome).1,122
Since the first description of pathogenic mutations in the mitochondrial genome, over 200 diseasecorrelated point mutations and rearrangements
have been found in association with a variety of
mitochondrial cytopathies.88 More than half of these
mutations have been located in tRNA genes that
MUSCLE & NERVE
February 2008
constitute ⬃9% of the entire mitochondrial genome.91 Thus, mitochondrial tRNA genes are hotspots for mitochondrial pathogenesis and contribute
in a disproportionate way to the etiology of disorders
caused by mitochondrial DNA mutations, which is
conceivable due to their central role in mitochondrial protein synthesis. In comparison, a little less
than half of the mitochondrial mutations affect protein coding genes, which comprises 68% of the entire mitochondrial genome.42
To achieve their goal of carrying amino acids for
protein synthesis, these tRNA molecules have to undergo different steps of processing and modification, and interact with many protein factors.128 Disease-related mutations could potentially affect the
primary, secondary, and tertiary structures of a given
mitochondrial tRNA. Misfolding and instability of
the mutant tRNA result in increased degradation
and ultimately lead to decreased steady-state levels of
a mitochondrial tRNA. In addition, the efficiency of
the aminoacylation process will be particularly sensitive to point mutations because the enzymes involved recognize a specific structure of a tRNA.196
There are still many unanswered questions regarding the phenotypic effect of these mutations.
Perhaps one of the most intriguing is the incredible
diversity of clinical phenotypes associated with mitochondrial tRNA mutations. This is a phenomenon
that has been observed even among individuals harboring the same mutation. Several factors including
the percentage of heteroplasmy, the different tissues
affected with the mutation, the position of the
mutation within the structure of the tRNA gene, the
efficiency in the utilization of different codons
for the same amino acid, and the different amino
acid composition among the mitochondrial DNAencoded protein subunits may account for this variability. In addition, nuclear genes, different mitochondrial genetic backgrounds, and environmental
factors may also exert a modifier effect.
The aim of this review is to focus on the assessment of pathogenic mitochondrial tRNA mutations,
the pathogenic mechanism of disease of known and
well-established mutations, the description of new
pathogenic mutations, and the elucidation of their
clinical significance.
CANONICAL CRITERIA FOR ASSESSING
PATHOGENICITY OF MITOCHONDRIAL tRNA
MUTATIONS
MtDNA alterations can be divided into three classes:
pathogenic, adaptive (advantageous in certain environments), and neutral (accumulated by chance).
Human Mitochondrial tRNAs
Most of the observed mtDNA changes represent neutral polymorphisms and have been used to track
human migrations.70 The large prevalence of variations in tRNA genes calls for the elucidation of their
pathogenicity. In addition, clinical misattribution of
pathogenicity is an important issue due to the consequences for genetic counseling that is provided to
individuals and families with mitochondrial disease.
Benign variants can be mistaken as bona fide pathogenic mutations when found in one or a limited
number of individuals, especially if present in the
heteroplasmic state, which has been regarded as direct evidence for pathogenicity.
A set of rules had to be established to confirm the
pathogenic nature of novel mtDNA mutations. Di
Mauro and Schon35 have previously described the
canonical pathogenic criteria for mtDNA point mutations. These rules specified that the mutation
should (1) be absent in healthy subjects, (2) alter an
evolutionary conserved residue, (3) be heteroplasmic and segregate with disease, (4) be such that the
degree of mutant heteroplasmy correlates with clinical severity and cell pathology as documented by
single-fiber polymerase chain reaction (PCR), and
(5) cause defects of mitochondrial protein synthesis
and respiratory chain deficiencies in single or multiple affected tissues of patients and demonstrable in
cybrid cell lines. Cybrid cell lines are generated by
transferring mitochondria isolated from patients
harboring pathogenic mutations into cultured human cells treated with ethidium bromide to deplete
their mitochondrial DNA.81
However, some pathogenic mtDNA mutations
fail to meet these established canonical criteria. In
particular, the homoplasmic mutations often do not
demonstrate the required segregation with either
biochemical deficiency or clinical disease. It is now
known that homoplasmic mitochondrial tRNA mutations can be pathogenic, as demonstrated with
several mutations in the tRNASer(UCN) gene,72 the
1624 C⬎T mutation in the tRNAVal that caused multiple neonatal deaths and Leigh syndrome in the
offspring of a homoplasmic and mildly affected
woman,100 the 4291 T⬎C in the tRNAIle gene associated with hypertension and dyslipidemia,195 the
4300 A⬎G in the tRNAIle gene responsible for maternally inherited cardiomyopathy in two families,173
and the 5693 T⬎C change in the mitochondrial
tRNAAsn gene that caused encephalomyopathy.27 In
addition, true pathogenic mutations may escape
identification because of poor evolutionary conservation in the region or because segregation with
disease cannot be demonstrated in small families.
MUSCLE & NERVE
February 2008
151
In order to take into consideration these known
exceptions to the canonical criteria, newer classification systems have been proposed by different
groups. Mitchell et al.108 designed a scoring system
to assess the pathogenicity of a given sequence variant in the mitochondrial encoded complex I
(MTND) subunit genes. Another scoring system specific for the mitochondrial tRNA gene mutations
listed on MITOMAP was devised by McFarland et
al.101 with specific scoring criteria that gave higher
scores to transmitochondrial cybrid experiments,
measurements of steady-state levels, and segregation
of the mutation with a biochemical defect at the level
of single cell.
CRITERIA FOR ASSESSMENT OF PATHOGENICITY OF
mtDNA ALTERATIONS AND CLASSIFICATION OF
MUTATIONS
We evaluated the mitochondrial tRNA mutations
listed on MITOMAP, which is the largest publicly
available compendium of mtDNA mutations and
polymorphisms (MITOMAP: A Human Mitochondrial Genome Database; http://www.mitomap.org
accessed on January 31, 2007). In addition, we
searched PubMed (http://www.ncbi.nlm.nih.gov/
entrez accessed January 31, 2007) in order to analyze
a thorough and complete list of mitochondrial tRNA
gene mutations.
Since the determination of the pathological significance of these mitochondrial tRNA variants is
required in order to provide accurate genetic services, we evaluated the mutations in the mitochondrial tRNA genes using a modified scoring system by
taking earlier scoring systems101,108 into consideration. Functional studies including steady-state levels
of mutated mitochondrial tRNA, evidence of pathogenicity from cybrid cells or single fiber studies, were
given the highest scores. We did not score the presence of positive single fibers additively since the
levels of the mutant tRNA would be higher in COXnegative fibers than in adjacent COX-positive fibers
if there is a decline in steady-state mRNA level or
evidence of pathogenicity from transmitochondrial
cybrid studies. Positive evidence from any of these
experiments was scored a maximum of 9 points. The
presence of strong histochemical evidence including
COX-negative ragged-red fibers or cristae abnormalities by electron microscopy was assigned 5 points.
The respiratory chain (RC) defects were classified
according to the modified Walker criteria8 and a
score of 5 or 3 points was given for fitting major or
minor criteria, respectively. Evolutionary conservation weighed second to functional evidence, with a
152
Human Mitochondrial tRNAs
maximum of 8 points. The nucleotide sequences
from yeast (Saccharomyces cerevisiae), sea urchin
(Strongylocentrotus purpuratus), fruit fly (Drosophila
melanogaster), frog (Xenopus laevis), mouse (Mus musculus), cattle (Bos taurus), and human (Homo sapiens)
were compared. One point was subtracted for each
nucleotide variation occurring in the species listed
above. One additional point was subtracted for variations that occurred in each of the four adjacent
nucleotides. For nucleotides in the stem region,
their complementary nucleotides rather than the
adjacent nucleotides were considered. The existence
of more than one independent report and the presence of heteroplasmy were given 5 points each.
Three points were given for segregation of the mutation with the disease (Table 1). For each mutation,
references were evaluated according to the criteria
described above and a score was given. If an experiment was not performed or the data were not provided for any reason, a score of 0 was given to that
criterion. Based on our scoring system, each mutation could receive a maximum score of 40.
Overall, the variations in the mitochondrial
tRNA genes that were classified according to these
new criteria were assigned to four distinct categories:
(1) definite pathogenicity (ⱖ30 points), (2) probable pathogenicity (20 –29 points), (3) possible pathogenicity (10 –19 points), and (4) unlikely pathogenicity (ⱕ9 points). The scores listed in Table 2
represent the minimal scores since not all the relevant experiments to confirm pathogenicity were performed in each case.
Table 1. Scoring criteria applied to mitochondrial tRNA mutations
listed on MITOMAP and PubMed.
Score
(points)
Pathogenic criteria
Evolutionary conservation of the base
More than one independent report
Presence of heteroplasmy
Histochemical evidence
RC defects (in tissues)
Segregation of mutation with the
disease
Single fiber studies, or steady-state
levels, or cybrid studies
No change
Each change
Yes
No
Yes
No
Strong evidence
Weak evidence
No evidence
Strong
Moderate
No
Yes
No
Yes
No
8
⫺1
5
0
5
0
5
3
0
5
3
0
3
0
9
0
RC, respiratory chain.
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February 2008
Table 2. Structural distribution of tRNA mutations and clinical phenotype.
tRNA gene
Nucleotide
change
Region
MTTF
MTTF
MTTF
MTTF
MTTF
MTTF
MTTV
582 T⬎C
583 G⬎A
608 A⬎G
611 G⬎A
618 T⬎C
622 G⬎A
1606 G⬎A
Acceptor stem
Acceptor stem
AC stem
AC wobble base
AC stem
Variable loop
Acceptor stem
MTTV
MTTV
MTTV
MTTV
1624 C⬎T
1642 G⬎A
1644 G⬎T
1659 T⬎C
DHU stem
AC stem
Variable region
T␺C stem
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTL (UUR)
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTI
MTTQ
MTTQ
3243 A⬎G
3243 A⬎T
3249 G⬎A
3250 T⬎C
3251 A⬎G
3252 A⬎G
3254 C⬎G
3255 G⬎A
3256 C⬎T
3258 T⬎C
3260 A⬎G
3264 T⬎C
3271 T⬎C
3271 delT
3273 T⬎C
3274 A⬎G
3280 A⬎G
3287C⬎A
3288 A⬎G
3291 T⬎C
3302 A⬎G
3303 C⬎T
4267 A⬎G
4269 A⬎G
4274 T⬎C
4284 G⬎A
4285 T⬎C
4291 T⬎C
4295 A⬎G
4298 G⬎A
4300 A⬎G
4309 G⬎A
4317 A⬎G
4320 C⬎T
4332G⬎A
4336 T⬎C
DHU loop
DHU loop
DHU loop
DHU loop
DHU loop
DHU loop
DHU stem
DHU stem
DHU stem
AC stem
AC stem
AC loop
AC stem
AC stem
AC stem
AC stem
T␺C stem
T␺C loop
T␺C loop
T␺C loop
AC stem
Acceptor stem
Acceptor stem
Acceptor stem
DHU stem
DHU/AC stem
AC stem
AC loop
AC stem
AC stem
AC stem
T␺C stem
T␺C loop
T␺C stem
Acceptor stem
Acceptor stem
MM
MTTM
Het
4409 T⬎C
30
DHU stem
MTTM
MTTW
MTTW
MTTW
MTTW
4450 G⬎A
5521 G⬎A
5532 G⬎A
5537 InsT
5540 G⬎A
T␺C stem
DHU stem
DHU stem
AC stem
AC stem
Human Mitochondrial tRNAs
Clinical features of related
pathologies
M.M., EI, tachycardia
MELAS, EI, RP
TIN
MERRF
MM
EI
Ataxia, PEM, SNHL, Sz, RP,
cataracts, hypotonia
Adult LS
MELAS
LS
Movement disorder,
hemiplegia
MELAS, DM, SNHL
PEM, MM
KSS
MM
MM
MELAS
MM
MERRF/KSS overlap
MERRF, MELAS
MM
MM, HCM
DM
MELAS, DM
PEM
PEO, EI
Depression, cataracts
MM
PEM, RP, SNHL
MM
MELAS
MM
HCM
MM, ataxia, SNHL
DCM, Sz, SNHL, FSGS
CPEO, ALS
CPEO, HCM
PEO
HTN, dsylipidemia
HCM
CPEO, MS, MM
HCM
CPEO
DCM
PEM, HCM
Atypical MELAS, DM
Alzheimer
disease/Parkinson
disease
S (male)
EI, muscle atrophy,
hypotonia, short stature
Splenic lymphoma
MM
MNGIE-like syndrome
MILS
PEM
Het/Hom
Score
Inheritance
References
Het
Het
Homo
Het
Het
Het
Het
35
38
11
35
26
31
27
S (female)
D
I
D
D
D/I
I, D
112
30,57
184
94
85
33
130,178
Homo
Het
Het
Het
27
26
21
16
I
D
I
I
100
31
21
12
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het/homo
Het
Het
Het
Het
Het
Homo
Het
Het
Homo
Het
Het
Het
Het
Homo
40
21
26
18
25
28
13
35
40
39
40
10
27
21
35
33
40
33
21
21
40
29
30
27
37
22
26
21
21
38
34
27
33
13
30
15
I
ND
I
I
I
I
I
I
I, D
I
I
I
I
D
I
D
I
ND
I
D
I
I
D
I
ND
I
ND
I
I
S (female)
I
ND
ND
ND
D
ND
25
150
147
49
168
111
78
115
75,110
18,163
98
166
132
152
17
73
18,163
3
54
50
11,187
48,155
172
170
13,23
26
156
195
105
29,171
20,173
43
169
134
6
39
34
Het
30
D
190
Het
Het
Het
Het
Het
27
35
34
38
32
ND
I
I
I
ND
92
157
96
137, 182
158
MUSCLE & NERVE
February 2008
153
Table 2. Continued
tRNA gene
Nucleotide
change
Region
Clinical features of related
pathologies
Het/Hom
Score
Inheritance
References
Het
Het
Het
Het
35
23
34
33
D
ND
I
I
3
113
167
160
Het
32
I
40,66
Het
Homo
36
28
ND
ND
143
27
Het
Het
Het
Het
Het
35
32
34
26
39
D
ND
D
I
I
161,163
61,192
106
38
76,95,136
Homo
Het
Het
Het
Homo
16
35
26
35
20
I
S (female)
I
S (female)
I
138
123
131
126
119
MTTW
MTTW
MTTA
MTTA
5543 T⬎C
5549 G⬎A
5591 G⬎A
5628 T⬎C
AC loop
AC stem
Acceptor stem
AC stem
MTTA
5650 G⬎A
Acceptor stem
MTTN
MTTN
5692 T⬎C
5693 T⬎C
AC loop
AC loop
MTTN
MTTN
MTTN
MTTC
MTTC
5698 G⬎A
5703 G⬎A
5728 T⬎C
5783 G⬎A
5814 T⬎C
AC loop
AC stem
Acceptor stem
T␺C stem
DHU stem
MTTY
MTTY
MTTY
MTTY
MTSS1
(UCN)
MTSS1
(UCN)
MTSS1
(UCN)
MTTS1(UCN)
5843 A⬎G
5874 T⬎C
5877 C⬎T
5885 DelT
7443 A⬎G
T␺C loop
DHU stem
DHU loop
Acceptor stem
Acceptor stem
MM
Dementia, chorea, DM
MM, myalgia, high CK
CPEO, weakness,
dysphagia
MM, myotonic dystrophylike phenotype
CPEO
PEM, hypotonia, liver
dysfunction
CPEO, MM
CPEO, MM
FSGS, GH deficiency, PEM
MM, HCM, TIN, SNHL
MELAS, Sz, PEO, ataxia,
HCM
FSGS
EI, weakness
CPEO
CPEO
SNHL
7444 G⬎A
Acceptor stem
SNHL
Homo
20
I
119
7445 A⬎C
Acceptor stem
SNHL
Homo
15
I
119
7445 A⬎G
Acceptor stem
Het/homo
32
I
127, 149
MTTS1(UCN)
MTSS1
(UCN)
MTSS1
(UCN)
MTTS1(UCN)
MTTS1(UCN)
MTTS1(UCN)
MTTS1
(UCN)
MTTD
7472insA
7472insC
Variable region
Variable region
SNHL, palmoplantar
keratoderma
Sz
SNHL, MERRF, EI
Homo
Het
40
40
I
I
72
124,177
7480A⬎G
AC loop
Het
35
D
9
7497G⬎A
7510 T⬎C
7511 T⬎C
7512 T⬎C
DHU stem
Acceptor stem
Acceptor stem
Acceptor stem
MM, SNHL, dementia,
ataxia
MM, PEM, EI
SNHL
SNHL
PEM
Het/homo
Het
Homo
Homo
29
15
40
23
I
I
I
I
51,72
68
22,164
72
7526 A⬎G
MM
Het
26
S (female)
148
Sz, DD
DM, SNHL, MERRF,
MELAS
EI
MNGIE-like syndrome
Movement disorder
EM
PEO, movement disorder
MERRF
HCM
CPEO, MM, hypoventilation
MERRF, MELAS, SNHL
MERRF
MM
MERRF
HCM
CIP, CPEO
Het
Het
22
21
I
ND
154
133
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Het
Nd
22
27
16
35
27
38
8
32
38
33
32
35
21
5
I
D
I
D
S (female)
I
I
ND
I
I
ND
I
I
ND
46
189
198
67
179
7
175
163
99
129
163
118
104
89
MTTD
MTTK
7543 A⬎G
8296 A⬎G
connector region
(between
acceptor/D
stem)
AC stem
Acceptor stem
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTK
MTTG
MTTG
8300 T⬎C
8313 G⬎A
8326 A⬎G
8328 G⬎A
8342 G⬎A
8344 A⬎G
8348 A⬎G
8355 T⬎C
8356 T⬎C
8361 G⬎A
8362 T⬎G
8363 G⬎A
9997 T⬎C
10006 A⬎G
Acceptor stem
DHU stem
AC stem
AC stem
T␺C stem
T␺C loop
T␺C loop
T␺C stem
T␺C stem
Acceptor stem
Acceptor stem
Acceptor stem
Acceptor stem
DHU loop
154
Human Mitochondrial tRNAs
MUSCLE & NERVE
February 2008
Table 2. Continued
tRNA gene
Nucleotide
change
Region
MTTG
10010 T⬎C
DHU stem
MTTG
MTTR
MTTH
10044 A⬎G
10438 A⬎G
12147 G⬎A
T␺C loop
AC loop
DHU stem
MTTH
12183 G⬎A
T␺C stem
MTTH
MTTS2
(AGY)
MTTS2
(AGY)
MTTL (CUN)
MTTL(CUN)
MTTL (CUN)
MTTL (CUN)
MTTL (CUN)
MTTL (CUN)
MTTL (CUN)
MTTE
MTTE
MTTE
12192 G⬎A
12246 C⬎G
Clinical features of related
pathologies
Het/Hom
Score
Inheritance
References
Het
40
ND
10,29,114
Het
Het
Het
13
21
40
I
I
D
135
185
103, 174
Het
30
I
28
T␺C stem
T␺C loop
EM, MM, polyendocrine
dysfunction
EM
EM
MELAS, MERRF, cerebral
edema
RP, SNHL, muscle atrophy,
ataxia
HCM, DCM
CIP, CPEO
Homo
Homo
11
5
ND
ND
151
89
12258 C⬎A
Acceptor stem
DM, SNHL
Het
35
I
93, 97
12276 G⬎A
12297 T⬎C
12301 G⬎A
12311 T⬎C
12315 G⬎A
12320 A⬎G
12334 G⬎A
14687 T⬎C
14696 A⬎G
14709 T⬎C
DHU stem
AC loop
AC loop
Variable loop
T␺C stem
T␺C loop
Acceptor stem
T␺C loop
DHU stem
AC loop
Het
Het
Het
Het
Het
Het
Het
Het
Het
Homo
16
26
15
18
38
35
35
31
21
40
ND
I
S (male)
ND
D
ND
S (female)
S (male)
I
I
MTTE
14710G⬎A
AC (E⬎K)
Het
35
D
19
53,176
47
63
44, 77
194
191
16
185
56, 59,
102, 107
3
MTTT
15915 G⬎A
AC stem
Het
21
D
116,144
MTTT
MTTT
MTTT
15923 A⬎G
15940delT
15950 G⬎A
AC loop
T␺C loop
Acceptor stem
Homo
Homo
homo
0
0
0
I
I
ND
14
145
52
MTTP
MTTP
MTTP
15990 C⬎T
15995 G⬎A
16002 T⬎C
AC (P⬎S)
AC stem
DHU stem
CPEO
DCM
AISA
CPEO
MM, PEO
MM
M.M.
MM, HCM, RP
EM
DM, SNHL, FSHD, hydrops
fetalis
CPEO, fatigue, weakness,
EI
Sz, SNHL, MR, movement
disorder
LIMM
MM
Alzheimer
disease/Parkinson
disease
MM, CPEO
Movement disorder
Ptosis, CPEO
Het
Het
Het
35
15
19
S (female)
D
S (male)
71
198
146
AC, anticodon; AISA, acquired idiopathic sideroblastic anemia; ALS, amyotrophic lateral sclerosis; CIP, chronic intestinal pseudoobstruction; CPEO, chronic
progressive external ophthalmoplegia; D, de novo; DCM, dilated cardiomyopathy; DD, developmental delay; DHU, dihydrouridine; DM, diabetes mellitus; EI,
exercise intolerance; EM, encephalomyopathy; FSGS, focal segmental glomerulosclerosis; FSHD, facioscapulohumeral muscular dystrophy; GH, deficiency
growth hormone deficiency; HCM, hypertrophic cardiomyopathy; Het, heteroplasmy; Homo, homoplasmy; I, inherited; KSS, Kearns Sayre syndrome; LIMM,
lethal infantile mitochondrial myopathy; LS, Leigh syndrome; MELAS, mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes syndrome;
MERRF, myoclonic epilepsy associated with ragged-red fibers; MILS, maternally inherited Leigh syndrome; MM, mitochondrial myopathy; MNGIE, mitochondrial
neurogastrointestinal syndrome; MR, mental retardation; MS, multiple sclerosis; ND, not determined; PEM, progressive encephalomyopathy; PEO, progressive
external ophthalmoplegia; RP, retinitis pigmentosa; S, sporadic; SNHL, sensorineural hearing loss; Sz, seizure disorder; TIN, tubulointerstitial nephritis.
Note: tRNAs for pro, glu, ser(UCN), tyr, cys, asn, ala, and gln are transcribed from the light strand. The nucleotide changes listed in Table 2 refer to the
nucleotide and position in the mitochondrial DNA sequence as shown in http://www.mitomap.org
We also listed the nucleotide changes, the regions in the tRNA cloverleaf structure where these
mutations were present, and the assigned clinical
phenotype for these mutations (Table 2).
PATHOGENIC MUTATIONS AND BENIGN VARIANTS
Based on the newly adopted classification, among all
the tRNA mutations analyzed in this study there was a
small percentage of mutations that were classified as
neutral polymorphisms (6 of 124, 4.8%), whereas the
Human Mitochondrial tRNAs
remainder of the mutations were classified as possibly
(18 of 124, 14.5%), probably (40 of 124, 32.3%), and
definitely (60 of 124, 48.4%) pathogenic (Table 3).
Only the mutations with definite and probable pathogenicity (scoring 20 points or above) were further reviewed for the purpose of this study.
Mitochondrial tRNAPhe Mutations.
Mutations in this
gene have presented with a myopathic phenotype
in the affected subjects. Four heteroplasmic muta-
MUSCLE & NERVE
February 2008
155
Table 3. Distribution of pathogenic mutations and benign variants among mitochondrial tRNA genes.
Definite
(ⱖ 30)
Probable
(20–29)
Possible
(10–19)
Benign
variation
(ⱕ 9)
Total
Definite ⫹ probable
N (% total)
Predominant
Phenotype
F
V
L(UUR)
I
Q
M
W
A
N
C
Y
S(UCN)
D
K
G
R
H
S(AGY)
L(CUN)
4
0
10
5
2
1
5
3
4
1
2
5
0
7
1
0
2
1
3
1
4
9
6
0
1
1
0
1
1
1
4
2
4
1
1
0
0
1
1
1
3
1
1
0
0
0
0
0
1
2
0
1
1
0
1
0
3
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
0
0
1
0
6
5
22
12
3
2
6
3
5
2
4
11
2
13
4
1
3
2
7
5 (83%)
4 (80%)
19 (86%)
11 (92%)
2 (67%)
2 (100%)
6 (100%)
3 (100%)
5 (100%)
2 (100%)
3 (75%)
9 (82%)
2 (100%)
11 (85%)
2 (50%)
1 (100%)
2 (67%)
1 (50%)
4 (57%)
E
T
P
Total
3
0
1
60
1
1
0
40
0
0
2
18
0
3
0
6
4
4
3
124
4 (100%)
1 (25%)
1 (33%)
100 (82%)
MM
Multisystemic/LS
MELAS/DM/SNHL/LS
CM, PEO
EM, MM
MM
MM/MNGIE/LS/EM
MM
PEO/MM
Multisystemic
MM/PEO
SNHL
MM
MERRF
EM
EM
Multisystemic
DM/SNHL
PEO/MM/CM/AISA
PEO/MM/DM/SNHL/
EM/HCM
EM
MM/PEO
tRNA
gene
See Table 2 for definition of abbreviations.
tions: 582 T⬎C, 583 G⬎A, 618 T⬎C, and 622 G⬎A
were identified in four unrelated patients with
mitochondrial myopathy112 and exercise intolerance.30 The 583 G⬎A mutation has also been reported in a patient with a MELAS-like phenotype.57
In a patient with typical clinical, histological, and
biochemical features of MERRF, Mancuso et al.94
reported a novel G⬎A transition in nucleotide position 611, affecting the wobble base. The finding of
this mutation revealed that MERRF syndrome is not
always associated with tRNALys mutations.
Mitocondrial tRNAVal Mutations.
Patients carrying
mutations in this gene have had either multisystemic
involvement or a clinical picture consistent with
Leigh syndrome. These include a 1642 G⬎A in a
MELAS patient, a 1644 G⬎T in a patient with Leigh
syndrome, a 1606 G⬎A in patients with multisystemic disorders, and a homoplasmic 1624 C⬎T mutation in a family with Leigh syndrome and incomplete penetrance. The G⬎A substitution at
nucleotide position 1606 was found on two occasions
by two groups confirming the pathogenicity of this
mutation.130,178 These two patients exhibited similar
clinical phenotype: hearing loss, followed by ocular,
156
Human Mitochondrial tRNAs
CNS, and skeletal muscle involvement with reduced
RC enzymes in skeletal muscle.
McFarland et al.100 described a family with a homoplasmic 1624 C⬎T mutation that resulted in several
neonatal deaths and one surviving child with Leigh
syndrome. The mother was minimally symptomatic,
but a severe biochemical defect was present in a deceased infant and the mother. The 1624 C⬎T change
affected a highly conserved basepair at the stem region
of the dihydrouridine (DHU) arm. In addition, there
was a striking reduction in the steady-state mitochondrial tRNAVal in different tissues obtained from some
of these patients. Northern blot analysis did not reveal
evidence of unprocessed intermediates from a large
polycistronic RNA unit pointing toward a fast degradation of the mutant tRNA, which would have a major
impact on mitochondrial protein synthesis. The
marked difference in phenotypic expression between
the mother and her children could not be explained
by the mtDNA mutation alone since it is homoplasmic
in every tissue of all matrilineal family members. Epigenetics or nuclear-encoded elements might act as
modifiers.
Mitochondrial tRNALeu(UUR) Mutations.
Mutations in
this gene are associated with diverse phenotypes in-
MUSCLE & NERVE
February 2008
cluding MELAS syndrome, myopathies, maternally
inherited diabetes and deafness, and sensorineural
hearing loss (SNHL). More than 22 point mutations have been identified in this 77 nucleotide
tRNALeu(UUR) gene. At least 19 of them are of probable or definite pathogenicity. The majority are located in the DHU and anticodon arms. Leucine is
the most frequently used amino acid in human mitochondrial-encoded proteins. The usage of UUR
and CUN codons is ⬃17%– 83%. The common 3243
A⬎G mutation alters a highly conserved nucleotide
and this mutation is predicted to cause a pronounced change in the structure of the tRNALeu(UUR). The impact of this structural change on
aminoacylation has been studied.120 Studies using
cybrid cell lines that are generated by transferring
mitochondria isolated from patients harboring
pathogenic mutations into cultured human cells
have detected decreased respiratory chain enzyme
activities.141 Moreover, additional studies have revealed defects in aminoacylation,74 protein synthesis,24 RNA processing,86 and levels of tRNA modification.202 Mitochondrial processing intermediates,
consisting of RNA species referred to as RNA19,
could play a significant role in this syndrome, as
pointed out in a recent review.139 These mitochondrial processing intermediates corresponding to the
16S ribosomal RNA (rRNA), tRNALeu(UUR), and
the nicotinamide adenine dinucleotide dehydrogenase subunit 1 (ND1) genes were observed in cybrid
cell lines expressing the 3243 A⬎G.82 Since 16S
rRNA is contained in precursor RNA19, this transcript could be incorporated into the ribosomes,
leading to ribosome stalling. The percentage corresponding to the 3243 A⬎G mutation in the processing intermediates is higher than the percentage observed in mtDNA, suggesting that the processing
intermediates that contain mutations may be more
difficult to process than their cellular counterparts.86,87
In addition, this tRNA molecule has unstable
structural domains, and one of the effects of the
3243 A⬎G mutation might be the formation of a
dimeric complex that interferes with the function of
the tRNA within the context of protein-RNA assembly.196 Since the DHU stem of human mitochondrial
tRNALeu(UUR) contains only two Watson–Crick pairs,
the dimerization of this tRNA caused by this mutation may lead to its disruption.
The observed reduction in complex I associated
with MELAS syndrome could be linked to a skewing
of the tRNALeu anticodon availability. The mitochondrial tRNALeu(UUR) gene harboring the common
MELAS mutation lacks the normal taurine modifica-
Human Mitochondrial tRNAs
tion (5-taurinomethyluridine) at the anticodon wobble position, substantially decreasing UUG(Leu)–
dependent protein synthesis.83 This mechanism
could explain the reduced translation of UUG-rich
genes such as ND6. Most other mitochondrial transcripts preferentially use the UUA(Leu) codon,
hence their translation is not substantially affected.84
Deficient wobble modification may be one of the
many factors responsible for the phenotypic features
of MELAS syndrome.
The morbidity and mortality of stroke-like episodes observed in MELAS syndrome could also be
associated with the presence of vessels strongly positive for succinate dehydrogenase (SSVs). These
SSVs positive for cytochrome c oxidase activity may
play an important pathogenic role.62,117 Although
there is decreased cytochrome c oxidase activity for
each individual mitochondrion, there is a high increase in mitochondrial mass in these SSVs that leads
to an increase in total cytochrome c oxidase activity.
Nitric oxide (NO) binds the active sites of cytochrome c oxidase and displaces the heme-bound
oxygen.193 This could lead to oxygen depletion in
the surrounding tissue and decreased unbound NO,
with an ensuing microvascular stroke-like pattern.
Thus, the stroke-like episodes observed in MELAS
syndrome could be caused by alterations in NO homeostasis resulting in microvascular damage.
Another common mutation in tRNALeu(UUR) is
the 3271 T⬎C mutation at the anticodon stem region, which is also associated with MELAS syndrome
and diabetes mellitus. In transmitochondrial cybrid
lines generated with this mutation, a lack of posttranscriptional modification,202 decreased steadystate levels,202 and abnormal intermediates of protein synthesis64 have been observed. The anticodon
stem of the tRNALeu(UUR) is a loosely structured unit
formed by four AU basepairs within the wildtype
tRNA.197 The high AU content of the anticodon
stem causes weakness in this domain and susceptibility to rupture when mismatch mutations such as the
3271 T⬎C is present. Chemical studies revealed that
the anticodon stem was denatured in the mutant.197
This mutation caused an in vitro aminoacylation
defect connected to Km abnormalities.197
Mitochondrial tRNAIle Mutations.
The mitochondrial
tRNAIle gene is the third most commonly mutated
among the mitochondrial tRNA genes. Among the
12 reported mutations, 11 of them score above 20.
The predominant clinical phenotypes associated
with mutations in this mitochondrial tRNA are isolated cardiomyopathy (4295 A⬎G, and 4300
A⬎G),20,105 and progressive external ophthalmople-
MUSCLE & NERVE
February 2008
157
gia (4274 T⬎C, 4285 T⬎C, 4298 G⬎A, and 4309
G⬎A).13,43,156,171 Other phenotypes such as combined cardiomyopathy and PEO (4284 G⬎A),26 multisystemic (4269 A⬎G),170 encephalomyopathic
(4267 A⬎G),172 and hypertension and dyslipidemia
(4291 T⬎C)195 have been described. Studies of disease-related tRNAIle mutations using cell lines revealed changes in tRNA stability in the presence of
the 4269 A⬎G mutation that affects an AU pair in
the acceptor stem of the human mitochondrial tRNA.Ile An accelerated tRNA degradation related to
the loss of structural integrity caused by the mutation
was observed.201
The 4285 T⬎C and the 4298 G⬎A mutations
(located in the anticodon stem) diminished the efficiency of aminoacylation by as much as 1,000fold.79 It was also found that mutant tRNAs were able
to inhibit the charging of the wildtype tRNAIle80.
Two studies have revealed that the cardiomyopathy-associated mutation 4317 A⬎G induces an aberrant secondary structure in the T-stem due to the
instability introduced by the native CA pair.32,180
This aberrant structure may decrease aminoacylation. It seems that for this class of mutations in this
particular tRNA, a weak structure may amplify the
effect of the mutation.
Mitochondrial tRNAGln Mutations.
Mutations in this
gene have been found in patients with either an
encephalomyopathic or myopathic presentation. A
heteroplasmic G⬎A transition at nucleotide 4332 in
the tRNAGln gene was identified in a subject presenting with stroke-like episodes, deafness, leukoencephalopathy, COX-negative ragged-red fibers, and basal
ganglia calcifications with late-onset findings that
were atypical for MELAS syndrome.6
Dey et al.34 reported a 12-year-old boy with a
myopathy in association with a single nucleotide insertion, 4370insA (T⬎AT), in the mitochondrial
tRNAGln gene. The muscle biopsy was remarkable, a
majority of the fibers were COX-deficient, and there
were decreased steady-state levels of subunit II of
COX and subunit 1 of complex I. Addition of the
extra nucleotide in the anticodon loop of this gene
changes seven evolutionary-conserved bases in the
anticodon loop to eight. In many cases, tRNAs with
eight or nine base anticodon loops have been associated with frameshifting.183 Occasional frameshift
during translation may lead to a defect in mitochondrial protein synthesis or misincorporation of amino
acids.
Mitochondrial tRNAMet Mutations.
A 4409 T⬎C mutation was found in a 30-year-old woman with exer-
158
Human Mitochondrial tRNAs
cise intolerance and dystrophic changes on skeletal
muscle.190 Because of the role of tRNAMet in translation initiation, the high level of the mutation observed in this patient’s skeletal muscle is likely to
cause a deficiency of mtDNA-encoded subunits, potentially affecting the capacity for ATP production.
In addition, a computerized analysis revealed a
markedly altered structure induced by this mutation.190
Another mutation, a G⬎A transition at position
4450 in this gene, was initially described by Lombes
et al.92 in a patient with splenic lymphoma. The
patient’s lymphocytes revealed abnormal mitochondria and multiple RC defects. Transfer of the mutant
mitochondria to Rho0 cells demonstrated a severe
respiratory defect. However the link of this mutation
to the underlying disease remains unclear.
Mitochondrial tRNATrp Mutations.
Six pathogenic
mutations have been reported in this tRNA gene and
cause a diverse clinical picture. A novel pathogenic
mutation 5521 G⬎A was found to be associated with
late-onset mitochondrial myopathy.157 Histochemical and biochemical studies documented COX-negative ragged-red fibers. This mutation located in the
D-stem could affect the tRNA-ribosome interaction,
resulting in reduced mitochondrial protein synthesis. Alternatively, since this mutation is located close
to the origin of mtDNA light-strand replication, it
could interfere with the regulation of the mtDNA
light strand, altering the L-strand secondary structure formed after the H-strand displacement.
The combination of Leigh syndrome, muscle
COX deficiency, complex I deficiency, and a heteroplasmic 5537 insertion T has been described on two
occasions in different families by two independent
groups.137,182 This mutation affects the structure and
stability of the anticodon stem region. Insertions in
the tRNA genes are a rare cause of mitochondrial
disorders, but these cases suggested that this mutation should be screened in cases of Leigh syndrome
and COX deficiency when mutations in SURF1 have
been excluded.
Other heteroplasmic point mutations in this
tRNA gene includes 5532 G⬎A in a patient with a
neurogastrointestinal syndrome,96 a novel pathogenic 5540 G⬎A transition in a patient with sporadic
encephalomyopathy characterized by spinocerebellar ataxia,158 a 5543 T⬎C causing mitochondrial myopathy, and a 5549 G⬎A mutation associated with
dementia, chorea, and diabetes. Complex IV deficiency may be the most common RC defect found in
patients affected with mutations in the mitochondrial tRNATrp gene. This finding may be explained
MUSCLE & NERVE
February 2008
by the higher relative content of tryptophan in COX
subunits COI and COIII, 3.1% and 4.6%, respectively, compared to an average of 2.5% in mtDNA
encoded complex I subunits.157
Mitochondrial tRNAAla. Mutations in this gene have
been associated with a myopathic phenotype. The
T⬎C transition at nucleotide position 5628 was identified in a patient with late-onset chronic progressive
external ophthalmoplegia (CPEO), dysphagia, and
mild proximal myopathy.160 Two mutations were
found at the amino acid acceptor stem region: the
5591 G⬎A and the 5650 G⬎A; both cause mitochondrial myopathy.66,40,167 Both mutations create a mismatched basepair that can be designated as G4:U69
and U6:G67 for 5650 G⬎A and 5591 G⬎A, respectively, according to the canonical structure. These
mismatches lie next to a G5:U68 wobble in the
amino acid acceptor stem of the tRNAAla molecule.
One role of the G5:U68 pair is to provide the tRNA
conformation that is most favorable for binding and
positioning the tRNA acceptor end at the enzyme
catalytic site.45 The gain of an additional wobble may
distort the conformation of the tRNA and render
that structure unsuitable for aminoacylation.
Mitochondrial tRNAAsn Mutations.
Mutations in this
gene have been associated either with a CPEO phenotype or with a myopathic phenotype. The first
mutation associated with an A to G substitution in
nucleotide position 5692143 was found in a patient
presenting with CPEO. The mutation could cause a
possible reorganization of the anticodon loop leading to inhibition of assembly of the ribosome-mRNAtRNA complex required for translation.
A de novo 5698 G⬎A mutation has been described in two patients presenting with a phenotype
consisting of isolated mitochondrial myopathy with
chronic progressive ophthalmoplegia.163,161
Two patients with early onset of progressive external ophthalmoplegia and fatigability were described to have the 5703 G⬎A mutation in the
tRNAAsn.61,192 Studies using transmitochondrial cybrid cell lines containing this mutation revealed impaired oxidative phosphorylation and protein synthesis with severe reduction in steady-state levels of
the tRNAAsn pool.61 This was accompanied by a conformational change in the tRNAAsn that may impair
aminoacylation.
In contrast, the patient described by Coulbault et
al.27 presented with an encephalomyopathy and did
not have features of CPEO. A T⬎C substitution at
position 5693 in the tRNAAsn gene was found in
blood and muscle. It was suggested that this muta-
Human Mitochondrial tRNAs
tion could affect the anticodon loop structure of the
tRNAAsn since it is located next to the anticodon
GUU.
Another mutation at nucleotide position 5728 in
the same tRNA gene was reported as the cause of
multiorgan failure.106
Mitochondrial tRNACys Mutations.
The 5783 G⬎A
was found in a patient with myopathy, cardiomyopathy, renal failure, and sensorineural hearing loss
(SNHL).38 Another pathogenic mutation is the 5814
T⬎C mutation reported independently by three
groups to be associated with MELAS syndrome and
with progressive external ophthalmoplegia in the
first two cases.76,95,136 This mutation shares similar
features with the 3243 A⬎G mutation in the tRNALeu(UUR)76 in that both mutations are located at the
D-stem/D-loop boundary (positions 14 and 13 at the
cloverleaf). These nucleotides seem to provide stability to the tertiary structure of mitochondrial
tRNAs and regulate the efficiency of aminoacylation.55
Mitochondrial tRNATyr.
Patients with mutations in
this gene predominantly exhibit a myopathic phenotype, but more cases are required in order to establish a genotype–phenotype correlation.
The first reported pathogenic mutation in this
gene123 was a somatic 5874 T⬎C transition in a
woman with exercise intolerance and bilateral ptosis.
The transition changed a highly evolutionarily conserved nucleotide and may alter the transcriptional
processing or translation of mitochondrial proteins.
This mutation may preferentially affect complex III
and IV. This finding could be explained by the fact
that the percentage of tyrosine residues is among the
highest in cytochrome b, COXI, and COX III subunits.
Two additional cases with CPEO, myopathy, and
exercise intolerance associated with mutations in
this tRNA gene were 5877 C⬎T and 5885delT.126,131
The 5885delT shortened the aminoacyl-acceptor
stem.126 Since this 7-basepair stem is strictly conserved among mammalian mitochondrial tRNATyr
and is a canonical feature of tRNA in general, a
deletion may impair the formation of a proper secondary and tertiary structure. The 5877 C⬎T mutation occurs at the DHU loop of this gene.131 This
mutation seems to alter an essential residue for the
configuration of the L-shaped tertiary structure of
tRNA. Studies using transmitochondrial cybrids revealed decreased oxygen consumption and compromised cell viability.
MUSCLE & NERVE
February 2008
159
Mitochondrial tRNASer(UCN).
Patients carrying mutations in this gene usually present with SNHL. The
mutations associated with SNHL include the 7443
A⬎G, 7444 G⬎A, 7445 A⬎G, 7472 insC, the 7480
A⬎G, and the T to C changes at nucleotide positions
7510, 7511, and 7512. The pathogenic mutations
located at the boundary between the termination
codon of COI and the 3⬘ end of the tRNASer(UCN)
gene (7443 A⬎G, 7444 G⬎A, and 7445 A⬎G) affect
the processing and stabilization of the precursor
tRNASer(UCN) rather than affecting the termination
codon of CO1.199 These mutations affect the secondary structure at the 3⬘ tRNA cleavage site for the
processing by tRNaseZL, leading to decreased steadystate levels of tRNA.90,200
The 7472 insertion C mutation was found in a
family who exhibited SNHL and a MERRF-like phenotype177 and in another patient with isolated myopathy, expanding the clinical phenotype of the mutation.124 The insertion adds a seventh cytosine to a
six-cytosine run in the T⌿C loop, potentially altering the secondary structure of the mitochondrial
tRNASer(UCN) gene. Analysis of cybrids containing
the 7472 insertion C revealed a decrease in the
abundance of this particular tRNA, suggesting that it
could be the result of altered processing.181
In addition, the 7480 A⬎G mutation was described in a woman who presented with a progressive
mitochondrial myopathy and later developed SNHL,
dementia, and ataxia.9 This mutation could
lengthen the anticodon stem by additional pairing,
drastically reducing the size of the anticodon loop,
and compromising anticodon function by the disruption of codon matching.
These SNHL-related tRNASer(UCN) mutations occurred multiple times on different genetic backgrounds at either heteroplasmic or homoplasmic
states, and the clinical severity does not appear to
correlate with the proportion of mutant heteroplasmy.22,68,69,186,188 In addition to hearing impairment, there are inter- and intrafamilial differences
in the penetrance of the neurological dysfunction.
These results and the lack of correlation between the
mutant load and the phenotype suggest that nuclear
genes may play a role in the clinical expression of
these mutations. Furthermore, the reason that these
mutations preferentially affect the function of the
inner ear is currently not known.
Interestingly, a heteroplasmic mutation in this
same tRNA, 7497 G⬎A, does not cause SNHL but
rather a mitochondrial myopathy.51,72 This mutation
has been reported in a 13-year-old girl with exercise
intolerance and lactic acidosis, and in another two
unrelated families with progressive myopathy,
160
Human Mitochondrial tRNAs
ragged-red fibers, lactic acidosis, and respiratory
chain complexes deficiency.51,72
tRNAAsp
Mutations. Two probable
pathogenic mutations in the tRNAAsp gene have
been reported. The first heteroplasmic pathogenic
mutation in this gene was reported154 in a patient
with myoclonic epilepsy and psychomotor regression
and other affected family members. The mutation
abolished a highly conserved pairing in the anticodon domain of the tRNAAsp gene that could affect
the double helix, resulting in an alteration of the
secondary structure of this tRNA. In addition, another pathogenic mutation in this gene was reported148 in a young girl who presented with isolated
progressive exercise intolerance.
Mitochondrial
The tRNALys is an
example of an oversimplified structure with a small
DHU loop. The small DHU loop may limit the number of contacts necessary to stabilize the tertiary fold
and the intrinsically weak structure of the human
mitochondrial tRNALys depends on the existence of
modified bases to maintain tRNA integrity. The existence of posttranscriptional modifications plays an
important role in stabilizing the structure of mitochondrial tRNALys. Proper folding and aminoacylation require a 1-methyladenine residue at nucleotide
9 to prevent formation of an alternative structure
with an extended acceptor stem.65
The 8344 A⬎G mutation located in this gene is
present in 80%–90% of patients with myoclonic epilepsy associated with ragged-red fibers (MERRF).36
Cybrid cells carrying this mutation demonstrated
reduced protein synthesis as a consequence of diminished tRNA stability and concomitant reduction
in the aminoacylation level for the mutant
tRNA.Lys37
It has also been found that the levels of posttranscriptional modification in the wobble position of
the anticodon tRNALys were decreased, leading to
disruptive translation.203 The disruption in translation was related to the defective binding of the mutant 8344 A⬎G to the mRNA-ribosome complex and
defective translation of both AAA and AAG codons
due to weak codon–anticodon interaction in this
mutant tRNA. Further work revealed lack of taurine
modification at the wobble uridine of mitochondrial
tRNALys from pathogenic cells of MERRF patients
carrying 8344 A⬎G mutation.165 The 2-thio group of
the wobble uridine is involved in mediating a stable
codon–anticodon interaction,4 hence the loss of the
2-thio group associated with this mutation is thought
Mitochondrial tRNALys Mutations.
MUSCLE & NERVE
February 2008
to be one of the main reasons for the weak binding
to cognate codons.
Two other pathogenic mutations in this same
gene, 8356 T⬎C and 8363 G⬎A, seem to account for
most of the remaining MERRF cases36 and more
recently the 8361 G⬎A has been added to the expanding mutational spectrum of MERRF.129 However, the clinical phenotype associated with mutations in this gene can be broad. The 8361 G⬎A
mutation has been associated with cardiomyopathy129 and other mutations in the same gene are
associated with exercise intolerance (8300 T⬎C),46
atypical MELAS (8296 A⬎G),133 and a phenotype
evocative of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome (8313
G⬎A).189 In addition, other clinical presentations
include encephalomyopathy (8328 G⬎A),67 myopathy (8362 T⬎G),163 PEO and myopathy (8355
T⬎C),163 and PEO with movement disorder (8342
G⬎A).179 The potential pathomechanistic effects of
the 8344 A⬎G mutation were studied in vitro and
the mutant transmitochondrial cybrids exhibited
poor respiration and defective mitochondrial protein synthesis and respiratory chain enzyme activity
in addition to a marked decrease in tRNALys steadystate levels and aminoacylation.5
Mitochondrial tRNAGly Mutations.
Two pathogenic
mutations in this tRNA gene have been reported.
The 9997 T⬎C mutation caused hypertrophic cardiomyopathy.104 The 10010 T⬎C mutation has been
associated with diverse clinical phenotypes that include an encephalomyopathic presentation with seizures, choreoathetosis, ataxia, and spastic tetraparesis10; a myopathic presentation with fatigue and
elevated serum creatine kinase114; and a multisystemic presentation with exercise intolerance, polyneuropathy, and hypothyroidism.29 This mutation is
located within a highly conserved stem region of the
DHU arm, which underlies its pathogenicity.
Mitochondrial tRNAArg Mutations.
The heteroplasmic 10438 A⬎G in the tRNAArg gene was found in a
boy affected with mild cognitive impairment, ataxia,
nystagmus, and muscle weakness.185 This mutation
changed the nucleotide flanking the anticodon.
Point mutations flanking the anticodon triplet may
affect codon matching and potentially tRNA synthetase recognition, ultimately leading to a decrease
in the accuracy and rate of translation.204 The position 10438 in mitochondrial DNA corresponds to
position 37 in the tRNA molecule. Through sequencing of human mitochondrial tRNAs, it is
known that this nucleotide undergoes posttranscrip-
Human Mitochondrial tRNAs
tional modification, which suggests functional relevance.15
Mitochondrial tRNAHis.
The heteroplasmic 12147
G⬎A mutation was found in a patient with a MELAS
phenotype that eventually evolved into a MELAS/
MERRF phenotype.103 The change most likely would
perturb secondary and tertiary structure.103 As previously described,60 mutations in the dihydrouridine
arm might cause mitochondrial dysfunction by impairing mitochondrial protein synthesis. This may be
pertinent for COIII, the richest polypeptide in histidine residues,103 which may account for the associated COX deficiency.
Another pathogenic heteroplasmic mutation in
tRNAHis is the 12183 G⬎A at the T stem region
identified in a patient with pigmentary retinopathy,
SNHL, muscle hypotrophy, and ataxia.28
Mitochondrial tRNASer(AGY) Mutations.
Two families
with novel 12258 C⬎A mutation in the tRNASer(AGY)
gene have been reported. In the first case the patient
had a history of cataracts, SNHL, cerebellar ataxia,
and diabetes.93 The second time the mutation was
reported in a large pedigree of five generations with
24 affected matrilineal family members presenting
with retinitis pigmentosa and progressive SNHL.97
The 12258 C⬎A substitution altered a highly conserved basepair in the amino acid acceptor stem that
potentially could affect the secondary and tertiary
structures and therefore the function of this
tRNA.162 It is interesting to note that the only reported pathogenic mutation in the tRNASer(AGY)
gene, 12258 C⬎A change, causes SNHL, similar to
mutations in tRNASer(UCN). It is not clear why mutations in the tRNASer genes predominantly cause
SNHL.
tRNALeu(CUN)
Mutations. The myopathic phenotype is predominantly associated with
the mutations in this tRNALeu(CUN). The 12297 T⬎C
mutation, located right next to the anticodon,
caused dilated cardiomyopathy. The heteroplasmic
12315 G⬎A mutation was diagnosed in a young
woman affected with exercise intolerance, bilateral
ptosis, and PEO.77 The mutation disrupts a highly
conserved G-C basepair in the T⌿C stem of the
molecule. This mutation had been previously reported in a middle-aged man who had developed
ptosis, CPEO, weakness, retinitis pigmentosa, hearing loss, and peripheral neuropathy.44
Another heteroplasmic mutation 12320 A⬎G affecting the T⌿C loop was identified in a patient with
an isolated skeletal myopathy.194 In vivo, this mutaMitochondrial
MUSCLE & NERVE
February 2008
161
tion increased over time from 70%–90%. Concurrently, the patient’s myopathy progressed from mild
to profound.
The somatic 12334 G⬎A mutation affecting the
acceptor stem was identified in a subject who exhibited an isolated skeletal myopathy.191 The patient
presented with exercise intolerance, ragged-red fibers, and deficiencies of complex III and IV in skeletal muscle.
Mitochondrial tRNAGlu Mutations.
A 14687 T⬎C somatic mutation affecting the T⌿C loop of the mitochondrial tRNAGlu was associated with mitochondrial myopathy, respiratory failure, COX-negative
ragged-red fibers, and complex I and IV deficiencies.16
The 14696 A⬎G mutation was detected in a patient with psychomotor retardation, hypotonia, dysphasia, combined complex I and III deficiencies,
and ragged-red fibers. This mutation changes a nucleotide in the DHU stem, creating a novel basepair
and reducing the wobble.185
The heteroplasmic 14709 T⬎C mutation in the
tRNAGlu gene has been reported several times, presenting with a very heterogeneous clinical phenotype including diabetes, myopathy, ataxia, congenital encephalopathy, and a presentation suggestive of
facioscapulohumeral muscular dystrophy.56,59,102
Some of the clinical diversity could be accounted for
by the intratissue variability of the mutant load, but
the involvement of nuclear factors cannot be discounted. It has been documented that the mutation
has attained homoplasmy within a family and in a
variety of tissues.102 Cybrid studies revealed that this
mutation alone was not sufficient to lead to impairment of mitochondrial function in these homoplasmic cybrid clones.121 Reduced levels of mutant
tRNAs were observed. This nucleotide located immediately next to the anticodon may be important to
maintain the stability of the tRNA for codon-binding.
The 14710 G⬎A mutation3 was associated with a
phenotype consisting of retinopathy, PEO, ptosis,
and mitochondrial myopathy. This mutation resulted in an anticodon swap from Glu (CUU) to Lys
(UUU) in this particular gene, potentially having an
effect on tRNA aminoacylation. This is one of the
few mitochondrial tRNA mutations that changes an
anticodon amino acid. The other one is the 15990
C⬎T in the tRNAPro gene, that changes to serine
(see below).109
Mitochondrial tRNAThr Mutations.
The only mutation
in the mitochondrial tRNAThr gene that meets crite-
162
Human Mitochondrial tRNAs
ria for probable pathogenicity is the 15915 G⬎A.
This mutation was found in a patient with mitochondrial encephalomyopathy, myoclonus, ragged-red fibers, and progressive calcification in the basal ganglia and cerebral atrophy.116,144
Mitochondrial tRNAPro Mutations. The 15990 C⬎T
mutation in the tRNAPro gene has been associated
with myopathy and CPEO.109 This mutation would
convert the proline anticodon into a serine anticodon resulting in altered charging properties and
impairment of aminoacylation. The tRNA anticodon
swap could affect protein synthesis by enhancing
misprocessing of polycistronic primary transcripts,
amino acid misincorporation, and reduced or defective charging of the mitochondrial tRNAPro gene.
This mutation could also have effects on the
posttranscriptional modification of other nucleotides and potentially lead to hypomethylation or no
methylation in nucleotide 37 in the mitochondrial
tRNAPro gene.15 This hypomodification may attenuate the severity of disease and act as a negative
determinant interfering with the recognition of a
tRNA by a noncognate aminoacyl-tRNA synthetase,125 leading to mischarging of the mutant
tRNA instead of a complete lack of charging.
ASCERTAINMENT BIAS
Mitochondrial tRNA mutations have been traditionally characterized by the focal accumulation of large
numbers of morphologically and biochemically abnormal mitochondrial that present as ragged-red
fibers on skeletal muscle histology.153 This finding
may have led to an ascertainment bias since screening for mutations in mitochondrial tRNA genes is
usually done when ragged-red fibers are found, perhaps contributing to the disproportionately large
number of reported mitochondrial tRNA mutations.
PATHOGENICITY AND LOCATION OF MUTATIONS IN
THE THREE-LEAVES CLOVER STRUCTURE OF tRNA
The different distribution patterns of pathogenic
and neutral variants in the tRNA structure may prove
useful in devising an algorithm to predict the pathogenic effects of novel mitochondrial tRNA changes.
After reviewing and scoring the published mutations for pathogenicity based on our scoring system,
it is apparent that a significant percentage of mutations are not supported by sufficient evidence to be
considered pathogenic. These are variations that
score below 20 points and are considered to be of
benign or possible pathogenicity. Of the listed mutations on MITOMAP and PubMed, 4.8% are con-
MUSCLE & NERVE
February 2008
sidered neutral variants. If we add the mutations with
possible pathogenicity (14.5%), it is found that
about 19% of the surveyed mutations either constitute benign variants or have weak evidence for
pathogenicity (Tables 3, 4). Some of these published
mutations were reported before the canonical criteria35 were established. It is interesting to note that in
the article published by McFarland et al.101 26% of
the reviewed mutations listed as pathogenic on
MITOMAP did not have enough evidence to be
considered pathogenic. The same group also stated
that only 16% of the analyzed mutations were pathogenic beyond doubt,101 in contrast to our review,
where around 48% of the analyzed mutations have
definite pathogenicity (Tables 3, 4).
The difference in results could be accounted by
the different scoring criteria used in both studies
and by the fact that their analysis only included
mutations listed on MITOMAP as pathogenic as of
December 1, 2003, whereas our review includes mutations listed on the same database as pathogenic as
of January 31, 2007. In addition, mutations retrieved
from PubMed and not contained in MITOMAP were
also included. The reports of newly described mutations have included a more careful functional analysis of their pathogenicity.
A small number of common mutations are responsible for the majority of mitochondrial disorders due to mitochondrial DNA mutations. Three
mitochondrial tRNAs (tRNAIle, tRNALeu(UUR), and
tRNALys) concentrate almost half (41%) of the
known mutations associated with definite and probable pathogenicity (Table 3). This finding has been
noted before,58 and the percentage found in our
review is in agreement with previous reviews196
where mutations in those three genes accounted for
almost half of the mutations deemed to be associated
with pathogenicity.
Among the three genes the tRNALeu(UUR) gene is
a hotspot for pathogenic mutations consistent with
the findings of a previous study.141 Moreover, we
observed the highest sequence variability (22 variants) and pathogenic mutation (definite plus probable) to nonpathogenic variant (possible plus unlikely) ratio (19:3 ⫽ 6.3) occurred in the
mitochondrial tRNALeu(UUR) gene. However, these
observations may also reflect an ascertainment bias
since, in some studies of mitochondrial patients with
defined clinical syndromes (MERRF, MELAS, mitochondrial myopathy, PEO, and Leigh syndrome),
only the mitochondrial tRNALeu(UUR) and tRNALys
genes were targeted to look for known mutations
previously associated with these particular clinical
phenotypes, thus ignoring the potential contribution of other mitochondrial tRNA genes to these
phenotypes. The distribution of pathogenic mutations encompasses all of the 22 mitochondrial tRNA
genes (http://www.mitomap/org) (Table 3).
Our review revealed that although the distribution of mitochondrial tRNA mutations includes any
domain of the cloverleaf structure, most of the
pathogenic mutations occur in stem structures since
among the 100 mutations (definite plus probable)
found in mitochondrial tRNA genes, 68% occurred
in stem structures. There was also a predominance of
possible pathogenic mutations in stem structures (12
of 18; 66.6%). In the case of benign polymorphisms,
mutations in loop structures (5 of 6; 83.3%) predominated over mutations in stem regions (1 of 6;
16.6%).
McFarland et al.101 also commented on the fact
that the majority of pathogenic mutations in tRNAs
are located in stem structures (73%), with mutation
hotspots in the anticodon and the aminoacyl acceptor stems.101 According to our review, 45 definite
and probable mutations (45 of 100; 45%) occur in
Table 4. Distributions of tRNA mutations according to affected region of cloverleaf structure.
Acceptor stem
AC stem
AC loop
T␺C stem
T␺C loop
DHU stem
DHU loop
Variable
Connector region (Acceptor/DHU stem)
DHU/AC stem
Total
Definite
(ⱖ 30)
Probable
(20–29)
Possible
(10–19)
Benign
(ⱕ 9)
Total
15
12
9
5
5
10
1
3
0
0
60
9
9
4
4
2
4
5
1
1
1
40
3
3
2
3
2
3
1
1
0
0
18
1
0
1
0
3
0
1
0
0
0
6
28
24
16
12
12
176
8
5
1
1
124
See Table 2 for abbreviations.
Human Mitochondrial tRNAs
MUSCLE & NERVE
February 2008
163
the acceptor and anticodon stems, edging closer to
50% of the total number of pathogenic mutations.
Alterations in these regions may exert significant
impact on codon binding and amino acid charging
thus impairing mitochondrial protein synthesis.
Few mitochondrial tRNA genes harbor mutations
in the loop structures. However, an exception occurs
in the mitochondrial tRNALeu(UUR) gene, where five
pathogenic mutations (one definite and four probable) are located in the dihydrouridine loop (DHU
loop) (see Table 2). Of interest, the structure of this
particular mitochondrial tRNA gene might explain
why mutations occurring in the loop may significantly affect the function. The tertiary structure of
this mitochondrial tRNA gene is different from the
structure of the cytosolic tRNAs and this difference is
achieved by a process of posttranscriptional modifications.159 This tRNA has the largest DHU loop and
a large T⌿C loop. An alteration in the base composition of these large loops may render this structure
vulnerable by altering the tertiary hydrogen bonds in
these loops that are critical in maintaining the stability of this tRNA molecule. Structural anomalies
caused by the 3243 A⬎G mutation were noted in the
folding of the DHU-arm of the mitochondrial
tRNALeu(UUR), but structural anomalies were not observed when the mutation was in the stem structure
as in the case of the 3271 T⬎C.159 Another example
of mutations that occur in large loop structures is the
8344 A⬎G mutation in the tRNALys gene. This mitochondrial tRNA has the largest T⌿C loop, and a
mutation in this structure may also affect the integrity of the tRNA. Thus, when pathogenic mutations
occur in loop structures, they tend to occur in loops
that are unusual in size and influence the tertiary
folding or function of the tRNA.
It is interesting to note that substitutions in the
anticodon triplet are extremely rare. Only three
pathogenic mutations, the 611 G⬎A in the tRNAPhe,
the 14710 G⬎A in the tRNAGlu, and the 15990 C⬎T
in the tRNAPro have been determined to affect any of
the three bases of the anticodon.3,94,109 The 611
G⬎A involves a wobble base change and it does not
change the amino acid to be charged. The other two
anticodon mutations indeed alter the amino acid to
be charged as specified by the tRNA. Due to the
fundamental role played by the anticodon in selecting tRNA identity, a high frequency of mutations is
not expected in these preserved residues, as they
would lead to lethal cellular consequences incompatible with life.
Although most of the pathogenic mitochondrial
tRNA mutations listed in Table 3 (definite plus probable) were found in highly conserved sites, consis-
164
Human Mitochondrial tRNAs
tent with previous studies,41,142,163 the known pathogenic 8344 A⬎G transition in the mitochondrial
tRNALys gene affects a nonconserved nucleotide.
This implies that the presence of a variant at a conserved site is not an absolute requirement to predict
its pathogenicity.41
At the level of the primary sequence the changes
introduced by the mutations in mitochondrial tRNA
genes are known to be mainly transitions (replacement of a purine by a purine or a pyrimidine by a
pyrimidine) rather than transversions (replacement
of a purine by a pyrimidine or vice versa). Upon the
analysis of our data we found that an overwhelming
majority of pathogenic mutations were transitions
(89%), with the remainder transversions (5%), and
deletions/insertions (6%). These findings support
the notion that transversions may be extremely detrimental from a cellular standpoint and that
“milder” changes are better tolerated.41 It is plausible to speculate that it might be easier to achieve a
transition than a transversion due to the structural
similarity. The predominance of chemically “mild”
mutations is a concept that was first introduced by
Florentz and Sissler.41 In addition, among the transitions there is a predominance of AG changes (57 of
89; 64%) when compared to TC changes (36%).
One of the most common oxidation products of
mtDNA, 8-oxoguanine, has been found at high levels
in human cells under conditions of oxidative stress,2
suggesting a possible role of oxidative stress in mitochondrial DNA damage and generation of mutations. However, it is not known whether this could be
one of the mechanisms responsible for the predominance of AG changes.
Although most of the mutations analyzed in this
review appeared to be inherited, eight patients were
found to exhibit somatic mutations that probably
arose during early embryonic development. In this
small cohort there was a predominance of females (8
of 11; 72.7%). However, more patients with somatic
mutations in mitochondrial tRNA genes will need to
be analyzed in order to know whether there is a clear
gender trend due to a biological mechanism that is
still elusive to us.
HOMOPLASMY OF PATHOGENIC MUTATIONS
Among the 100 pathogenic mutations described in
this review, 11 occurred in the homoplasmic state, in
which clinical expression and disease severity do not
correlate with mutant load in affected tissues. Apparently, nuclear genes play a role in the disease expression of these homoplasmic mutations. Homoplasmic
pathogenic mutations have also been reported in
MUSCLE & NERVE
February 2008
mitochondrial genes encoding for mRNAs. The increasing frequency of reports of homoplasmic mutations of definite and probable pathogenicity weakens
a rigid concept of heteroplasmy as sine qua non of
pathogenicity, requiring a more comprehensive
functional approach to clearly determine pathogenicity in these cases.
CORRELATION BETWEEN CLINICAL PHENOTYPE
AND NATURE OF tRNA MUTATION
There is a wide range of clinical manifestations that
are characteristic of disorders caused by mtDNA mutations, and in particular of patients harboring mutations in the mitochondrial tRNA genes. As described earlier, there appears to be little correlation
between the clinical manifestations observed in a
particular patient and the specific mitochondrial
tRNA harboring that mutation. However, mutations
at the same position in the cloverleaf structure of
different tRNA genes may be associated with similar
clinical phenotypes.142 Mutations at nucleotide position 4284 in the tRNAIle and at nucleotide position
5703 in the tRNAAsn, both at position 27 of the tRNA
structure, are associated with PEO. In addition, mutations at nucleotide position 3303 of the tRNALLys
eu(UUR) and nucleotide position 8363 of the tRNA
,
both at position 72, are associated with cardiomyopathy. Similarly, mutations at nucleotide position
4269 of the tRNAIle and at nucleotide position 9997
of the tRNAGly, both at position 7, are associated with
cardiomyopathy. Encephalomyopathy has been observed in association with mutations at nucleotide
positions 3271 of the tRNALeu(UUR) and 5549 of the
tRNATrp, which correspond to position 39. Lastly,
multisystemic involvement was observed with mutations at nucleotide positions 1606 of tRNAVal and
nucleotide position 7512 of tRNASer(UCN) that corresponded to position 5 of the cloverleaf structure.
These findings may add further evidence to support
the hypothesis that the genotype–phenotype correlation for tRNA mutations may be based on the
disruption of secondary and tertiary structures.
tRNA STRUCTURES ARE FRAGILE, SUSCEPTIBLE TO
DETRIMENTAL EFFECTS OF NUCLEOTIDE
SUBSTITUTIONS
In a previous review of mutations in mitochondrial
DNA encoded mRNA genes, 74 mutations scored as
probable or definite pathogenic in a total of 11,340
basepairs of 13 mRNA gene regions.199
In the current review, 90 pathogenic mutations
were found in a total of 1,505 basepairs coding for
tRNA genes. These data translate into 6.5 and 60
Human Mitochondrial tRNAs
mutations per kb for mRNA and tRNA genes, respectively. There is almost 10-fold higher frequency in
generating pathogenic mutations in tRNA genes
than in mRNA genes. If it is assumed that the mutation events occur randomly regardless of the nucleotide location, these results suggest that nucleotide
substitutions in tRNA genes are more detrimental
from a structural and functional standpoint than
mutations in mRNA genes. Nucleotide substitutions
in tRNA genes may affect their fragile structure,
unlike nucleotide substitutions in mRNA genes that
do not lead to a disruption in mitochondrial protein
synthesis.
CONCLUSIONS
Further analysis of an expanded series of tRNA mutants will be required in order to generate a consensus or framework that would allow the description of
the cellular and phenotypic effects of disease-related
tRNA mutations. It is important to consider the effects of pathogenic mutations on the structure of
mitochondrial tRNA genes because the structural
distortions probably underlie the biochemical and
clinical phenotypes observed in these patients. The
human mitochondrial tRNAs represent a class of
tRNAs with intrinsically weak structures that may be
the result of expedited evolution and streamlining of
the human mitochondrial genome. The inherent
conformational fragility and instability of these
tRNAs may amplify the effects of single-base substitutions, by disrupting a native conformation of structural elements or by promoting the formation of
intermediate, unstable, non-native structures.
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