Download 张咸宁_神经系统疾病的遗传学

Genetics of Neurodegenerative Disorders
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: C303, Teaching Building
2015/11
Required Reading
● Thompson &Thompson Genetics in Medicine, 7th Ed
（双语版，2009）
pp. 302-305, Chapter 12, The Molecular and
Biochemical Basis of Genetic Disease - Diseases due
to the Expansion of Unstable Repeat Sequences:
Biochemical and Cellular Mechanisms
Case Study, 15. Fragile X Syndrome
22. Huntington Disease
●Thompson &Thompson Genetics in Medicine,
8th ed., 2016
p. 242-254
Case 4, 17, 24
• 在已发现的单基因遗传病（www.omim.org）中，
半数以上累及神经系统。国内神经系统单基因遗
传病的发病率约为109.3/10万，其中以遗传性共济
失调和进行性肌营养不良最常见，神经系统遗传
性代谢缺陷病则以种类多、发病率低为特征
• 神经系统遗传病可在任何年龄发病。出生后：半
乳糖血症等；婴儿期：SMA1、Tay-Sachs病等；
儿童期：DMD等；少年期：肝豆状核变性、
SMA2等；青年期：腓骨肌萎缩症等；成年期：强
直性肌营养不良等；成年后期：Huntington舞蹈
症等；老年期：Alzheimer病等。多数神经系统遗
传病在30岁之前出现症状
• 神经系统遗传病病种繁多，致残和致畸率很高，
治疗困难
Classification of Neurogenetic Disorders
by Presentation
• Dementias（痴呆）
• Muscular dystrophies and atrophies
（肌营养不良和肌萎缩）
• Ataxias（共济失调）
• Mental retardation/dysmorphism
（精神发育迟缓/异形）
Classification by Molecular Defect
• Point mutations（点突变）
• Large deletions（大缺失）
• Trinucleotide repeat expansions（三核
苷酸重复突变）
• Mitochondrial DNA mutations（线粒
体DNA突变）
Neurodegenerative disorders
• Alzheimer disease
• Disorders of mitochondrial DNA
• Diseases due to the expansion of
unstable repeat sequences
Alzheimer disease
• generally manifests in the 6th to 9th decades
• a progressive deterioration of memory and of
higher cognitive functions, such as reasoning, in
addition to behavioral changes
• The lifetime risk: 12.1% in men and 20.3% in
women by age 85
• ~7%-10% of patients have a monogenic highly
penetrant form
• 4 genes: APP, PSEN1, PSEN2----autosomal
dominant
APOE----susceptibility gene
The Pathogenesis of Alzheimer Disease: βAmyloid Peptide and tau Protein Deposits
• Aβ peptide is generated from the larger
βAPP protein
• tau is a microtubule-associated protein
expressed abundantly in neurons of the
brain
• mutations in the tau gene are associated
not with AD but with another autosomal
dominant dementia, frontotemporal
dementia（额颞叶痴呆）
a coding mutation
(p.Ala673Thr) in
the APP gene can
protect against
both AD and
cognitive decline
in older adults
The Presenilin 1 and 2 Genes
• onset age:
PSEN1: 35 to 60 years
PSEN2: 40 to 85 years
• The basis of this variation is partly
dependent on the number of APOE ε4
alleles
The ε4 allele is significantly overrepresented in
patients with AD (≈40% vs. ≈15% in the general
population) and is associated with an early onset of
AD (for ε4/ε4 homozygotes, ~10 to 15 years earlier)
TREM2 gene (triggering receptor
expressed on myeloid cells 2)
• a fivefold increase in risk for late-onset
AD, making TREM2 mutations the
second most common contributor to
classic late-onset AD after APOE ε4
Genetic variants alter the risk for
AD in at least two general ways
• by modulating the production of Aβ
• through their impact on other
processes, including the regulation of
innate immunity, inflammation, and
the resecretion of protein aggregates
Trinucleotide repeat expansions are
dynamic mutations
• An unstable expanded repeat that
changes size between parent and
child.
The Pathogenesis of Diseases due to
Unstable Repeat Expansions
• Class 1: diseases due to the expansion of noncoding
repeats that cause a loss of protein expression--Fragile X Syndrome, Fragile X Tremor/Ataxia
Syndrome
• Class 2: disorders resulting from expansions of
noncoding repeats that confer novel properties on
the RNA---Myotonic Dystrophy
• Class 3: diseases due to repeat expansion of a codon
such as CAG (for glutamine) that confers novel
properties on the affected protein---Huntington
Disease
(A) In fragile X
syndrome, the expanded
repeat in the 5’ UTR of
the gene triggers
methylation of the
promoter and prevents
transcription.
(B) In myotonic
dystrophy, the expanded
repeat in the 3’ UTR
causes the mRNA
transcript to sequester
splicing factors in the
cell nucleus, preventing
the correct splicing of
several unrelated genes.
(C) In Huntington
disease, the gene
containing the expanded
repeat is transcribed
and translated as
normal, but the protein
product has an
expanded polyglutamine
tract that renders it
toxic.
Huntington Disease (Chorea)
• a progressive loss of motor control, dementia, and
psychiatric disorders. The brain area most
noticeably damaged is the corpus striatum. The
suicide rate among HD patients is >5~10 in the
general population.
• ~ 1 in 20,000 persons of European descent.
• usually manifests between the ages of 30 and 50
years, although it has been observed as early as 1
year of age and as late as 80 years of age.
Trinucleotide CAG repeat sizes in
HD gene (huntingtin)
•
•
•
•
Normal ≤26
Mutable 27-35
Reduced penetrance 36-39
Fully penetrance ≥40
Clinical Case
Mary (35 y.o.), Samuel (30 y.o.), and Alice
(29 y.o.) are siblings at 50% risk to inherit
Huntington disease from their father, John,
who was found to have a mutable normal
allele when he was tested following
diagnosis of his brother, Bart. All three
siblings chose molecular genetic testing
following genetic counseling and
neurologic evaluation. All have normal
neurologic examinations.
John
Mutable normal
Bart
Mary
38 CAG
repeats
Alice
42 CAG repeats
Samuel
35 CAG repeats
What do these results mean?
Diagnosis
Molecular Genetic Testing
Predominant Clinical Features of
Fragile X Syndrome in Males
Prepubertal
• Delayed developmental milestones: Sit alone, 10 mo; Walk,
20.6 mo; First clear words, 20 mo.
• Developmental delay
• Abnormal behavior: Tantrums; Hyperactivity; Autism
• Mental retardation: IQ 30 to 50
• Abnormal craniofacies: Long face; Prominent forehead;
Large ears; Prominent jaw
Postpubertal
• MR; Pronounced; Craniofacies; Macroorchidism
Additional Features
• Strabismus; Joint hyperextensibility; Mitral valve prolapse;
Soft, smooth skin
A: Two-yr-old male with a full mutation exhibiting a relatively
normal appearance with an elongated face and prominent ears;
also note tapering fingers, a minor anomaly.
B: At age 5 years, his head is large with large ears and a
prominent jaw.
C: At age 22 years.
CGG Repeat in Fragile X Syndrome
•
•
•
•
Normal range: 6-54
Premutation range: 52-200
Full mutation range: 200- >1000
Alleles with >200 repeats are
hypermethylated, transcriptionally
repressed
Risk of Expansion of Fragile X Premutations
Length of maternal
premutation
Incidence of full mutation in
offspring
56-59
13%
60-69
20%
70-79
58%
80-89
73%
90-99
94%
100-109
100%
120-129
100%
Nolin et al., Am J Hum Genet 1996
Is the fragile X premutation really
asymptomatic?
• Recent reports of premature ovarian
failure in female premutation carriers
• Late-onset tremor-ataxia-dementia
syndrome in male premutation carriers
• May be due to mRNA interference with
expression of the normal FMR1 allele or
of other genes
A New Fragile X Testing Dilemma
• Genetic counselors and obstetricians are
beginning to order fragile X carrier screening
on all pregnant women, regardless of family
history
• Unexpected premutation alleles are being
identified, leading to amniocentesis
• Pregnancies in which the fetus is found to have
only the premutation are typically continued
• The resulting child is now labeled with a lateonset genetic disease for which there is no
treatment
NIH Task Force on Genetic Testing
Myotonic Dystrophy
•
•
•
•
AD
Myotonia, muscular dystrophy
Cataracts, hypogonadism, frontal balding
Severe neonatal form due to dramatic
CTG repeat expansion from affected
mother only
Friedreich Ataxia
• AR
• The most common of the hereditary ataxias in
the Caucasian population.
• Gait disturbance in childhood
• Upper extremity ataxia
• Absent reflexes
• Intellectual decline
• Progressive cardiomyopathy
• Small proportion due to point mutations rather
than GAA repeat expansion
Unusual Aspects of Inheritance
of Trinucleotide Repeat Disorders
• Anticipation:
tendency toward earlier age of onset and/or greater
severity in each subsequent generation, due to
progressive expansion of the repeat length.
•
•
•
•
•
•
Parent-of-origin effects
Skewed X-inactivation
Methylation effects
Incomplete penetrance
Variable expressivity
Premutation alleles:
asymptomatic, but unstable, with a tendency to expand
in the next generation