Download Human Apolipoprotein A-l-C-lll Gene Complex is Located on

Human Apolipoprotein A-l-C-lll Gene
Complex is Located on Chromosome 11
Gail A. P. Bruns, Sotirios K. Karathanasis,
and Jan L. Breslow
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The genes for two of the apolipoproteins, apo A-l and apo C-lll, previously shown to
be within 3kb In the genome, were localized to human chromosome 11 by Southern
blot analysis of DNA from human-rodent somatic cell hybrids. These two genes were
shown to exhibit polymorphisms associated with dysllpoproteinemia and premature
atherosclerosis, and It will now be possible to examine the relationship of these genes
to the many others that have been assigned to this chromosome.
(Arteriosclerosis 4:97-102, March/April 1984)
ipoproteins are macromolecular complexes of
noncovalently bound lipid and apolipoproteins.
There are eight well-characterized apolipoproteins:
apo A-l, apo A-ll, apo A-IV, apo B, apo C-l, apo C-ll,
apo C-lll, and apo E.1 Regulatory or structural mutations in the genes specifying these apolipoproteins
may predispose individuals to dyslipoproteinemias,
some of which have been associated with premature
atherosclerosis. For example, variant apo E isoproteins due to amino acid substitutions in a receptor
binding region have been described, and are presumably due to apo E structural gene mutations.
These are common in the population and appear to
underlie susceptibility to Type III hyperlipoproteinemia, a disorder associated with defective chylomicron remnant removal, hypercholesterolemia, hypertriglyceridemia, xantnomatosis, and premature
atherosclerosis.2"10 Variant apo A-l isoproteins due
to amino acid substitutions have also been described, but are relatively rare.11"14 Recently, two
DNA polymorphisms in or near the apo A-l gene
locus have been described. In one situation apparent
homozygosity for the polymorphism was associated
with deficient plasma levels of apo A-l and apo C-lll,
high density lipoproteins (HDL), and severe prema-
ture atherosclerosis.1516 In the other situation a
group of severely hypertriglyceridemic patients with
Types IV and V hyperlipoproteinemia were shown to
have an increased incidence of a restriction fragment
length polymorphism (RFLP) associated with the
apo A-l gene.17
The cDNA and genomic clones for human apo A-l
and apo C-lll have been isolated and characterized,
and the genes specifying these two apolipoproteins
have been shown to be within 3kb in the genome and
convergently transcribed.18"22 Furthermore, the gene
lesion associated with apo A-l-apo C-lll deficiency
has been shown to be due to a large DNA insertion in
the coding region of the apo A-l gene,23 whereas the
RFLP associated with hypertriglyceridemia is explained by a single base substitution in the DNA corresponding to the 3' noncoding region of apo C-lll
mRNA.22 The chromosomal localization of these lesions will facilitate linkage studies to the RFLP map
being compiled for the human genome. This will aid
in family studies of atherosclerosis susceptibility;
also polymorphisms in the apolipoprotein genes may
prove to be valuable genetic markers in the study of
other linked genes.
From the Divisions of Genetics and Metabolism, Children's
Hospital Corporation, and the Department of Pediatrics, Harvard
Medical School, Boston, Massachusetts.
This work was supported in part by National Institutes of Health
Grants HD04807 and HL15895.
Address for reprints: Dr. Jan L. Breslow, Metabolism Division,
Children's Hospital Corporation, 300 Longwood Avenue, Boston,
Massachusetts 02115.
Received September 1, 1983; revision accepted November 3,
1983.
Methods
L
In the current study we investigated the chromosomal localization of the apo A-l-apo C-lll gene
complex. For this purpose we used a panel of DNA
from human-rodent somatic cell hybrids that have
been extensively characterized for human chromosome complements.24"27 The hybrids were derived
from fusions of HPRT deficient Chinese hamster E36
97
98
ARTERIOSCLEROSIS VOL 4, No 2, MARCH/APRIL 1984
Table 1. Hybridization Pattern of Apo A-l Probe with DNA Mapping Panels
Hybridization
Chromosome
+
+
-
+
+
Discordant fraction
Informative clones (no.)
Human chromosomes
1
2
3
4
5
6
7
10
8
11
8
8
11
9
3
13
12
8
11
10
8
8
4
7
3
7
7
4
5
3
3
6
3
5
7
8
0.23
30
0.33
30
0.32
28
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cells or mouse RAG cells with white blood cells or
fibroblasts from four unrelated individuals. Three of
the donors were female carriers of different balanced
X/autosome translocations and the fourth was a karyotypically normal male. Human chromosome complements of the hybrids used for DNA preparation
were determined by analysis of human isozyme
markers characteristic of each of the autosomes and
the X chromosome and by cytogenetic techniques.24"27 The latter included sequential Q-banding
and Giemsa 11-staining for the human-Chinese
hamster hybrids and sequential Q- and C-banding
for human-mouse hybrids. In addition, cloned cDNA
or genomic probes were used to monitor 19 of the
human autosomes and the X chromosome in DNA
from the mapping panels used in the present
study.24"27 DNA from the primary hybrid clones and
from the human and rodent parental cells were digested to completion with the restriction endonuclease EcoRI, electrophoresed on 0.8% agarose
gels, and transferred to nitrocellulose filters.28 Prehybridization and hybridization were carried out as previously described.16 The hybridization probes were
the inserts of clones pAI-113, pAI-101, and pCIII606,1822 excised with Pstl, and labelled with ^ P by
nick-translation. After hybridization for 15 to 20 hours
at 65°C, the excess probe was washed off by incubation in O.ixSSC and 0.1% SDS for 1 hour at 65 °C.
X-ray film was sandwiched between the filters and
an intensification screen and exposed at - 70° C for
3 days.
0.34
29
0.40
30
0.37
30
0.43
30
8
10
9
5
9
11
8
7
12
10
6
4
7
8
0.53
30
0.57
30
0.47
30
from cDNA clone pAI-101 that contained sequences
corresponding to the mRNA coding for apo A-l amino
acids - 4 to 143 (Figure 1). The 13kb component
characteristic of human DNA exhibited concordant
segregation with human chromosome 11 in all 30
primary human-Chinese hamster and human-mouse
hybrids in the DNA mapping panels. Chromosome
11 segregation in the hybrids was monitored by expression of the LDH-A and lysosomal acid phosphatase ACP-2 isozymes, hybridization of the DNA with
a cloned probe for beta-globin sequences,29 and cytogenetic identification of the chromosome. The hybridization pattern of the pAI-113 probe was discordant with the segregation of the other 21 autosomes
and the X and the Y chromosomes in the somatic cell
hybrids examined. The discordancy indices varied
from 0.23 to 0.57 (Table 1). In comparable studies,
the apo C-lll probe, pCIII-606, was also examined
and showed similar segregation characteristics.
Twenty-one independent human-mouse and human-hamster hybrid clones were examined for hybridization with the apo C-lll probe, pCIII-606, and
for their human chromosome complements by both
isozyme and cytogenetic techniques. In all 21
clones, the segregation of the apo C-lll hybridization
signal was concordant with that of the apo A-l probes
and of chromosome 11. The segregation of chromosome 11 in these hybrids was determined by analysis of the acid phosphatase ACP-2 isozymes, LDH-A
isozymes and coding sequence, beta globin sequences and by cytogenetic techniques. The discordancy fractions for apo C-lll and chromosomes 1 10,12-22, the X and the Y were 0.25-0.63 (Table 2).
Results
In our initial studies, the pAI-113 probe was used
as the hybridization probe with parental and hybrid
DNA. This DNA is approximately 500bp in length,
corresponds to the mRNA coding for apo A-l amino
acids 94 to 243 as well as to a portion of the apo A-l
mRNA 3' untranslated region, and in the genome is
uninterrupted by intronic DNA21 (Figure 1). After
EcoRI digestion, under the hybridization conditions,
the single 13kb component in human DNA was easily distinguishable from the single 2.2kb component in
Chinese hamster DNA, and from the two less intense
mouse components (Figure 1). Comparable hybridization patterns were observed with a probe made
Table 2. Segregation of Apo C-lll with Chromosome
11 In Human-Rodent Somatic Cell Hybrids
Chromosome 11
9
0
0
12
Apo C-l
APO A-l-C-lll ON HUMAN CHROMOSOME
99
Bruns et al.
Table 1. (Continued)
Human chromosomes
11
12
13
14
15
16
17
18
19
20
21
22
X
Y
15
11
9
10
9
9
4
7
13
10
12
8
15
1
15
8
6
5
8
9
7
9
2
7
6
7
0
14
0
4
6
5
6
5
10
5
2
5
3
6
0
13
8
9
7
15
0
0.46
28
0.50
30
7
0
0.37
30
00
30
7
10
7
5
0.46
28
0.50
30
0.43
30
0.36
28
i
i
o
1
•
i
4
0.56
25
r
f
i
13
0.50
30
'.
V
0.43
30
r
1
0.40
30
0.46
28
ID
~- . — KIII-tM
,''
P HI
HI
1i
5
0.38
26
.'
1
1 It'
unr
l
WU-Bl
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- PAI-113
A
CHROMOSOME
t
11
t
•
-
•
-
-
mm*
23.1
^1
23.1 -
94 _
6.5 _
4.2
432.3
2.0 •
2.32.0-
9
10TI
12131415
1617181920
B
Figure 1. A. Schematic representation of the region of the apo A-l-apo C-lll gene complex that corresponds to the apo AI and apo C-lll cDNA probes used in this study. Probe pAI-113 corresponds to apo A-l codons 94 to 243 (C. teminus) of apo
A-l mRNA and also includes a portion of the 3'-noncoding region. Probe pAI-101 corresponds to apo A-l codons - 4 to 143.
Probe pCIII-606 corresponds to apo C-lll codons 58 to 79 (C. terminus) and also includes the entire 3'-noncoding region of
apo C-lll mRNA and a part of the poly (A) tail. Restriction sites for EcoRI (R), BamHI (B), Hindlll (H3), PstI (P), and Hpall (H)
are indicated.
B. Hybridization patterns of probe pAI-113 and DNAs from human, rodent, and human-rodent somatic cell hybrids. The
DNAs are: Lane 1. Mouse RAG cells. Lane 2. Chinese hamster E36 cells. Lane 3. HeLa cells. Lanes 4-8,15,16.
Human-Chinese hamster hybrid clones. Lanes 9-14,17-20. Human-mouse hybrid clones. The cross-reactivity of pAI113 with rodent sequences is well visualized in Lanes 6-8 and 15, 16 (the hamster sequence) and Lanes 9 and 17 (the
mouse sequence). The difference in intensity of the hamster component in Lanes 15, 16 from that in Lanes 4-6 reflects a
difference in hybridization efficiency of the two blots resulting from differences in the DNA density per lane and in the transfer
conditions. Although not well visualized in Lane 2, the hamster component was observed in all E36 DNAs. In these two DNA
panels, the 13kb human apo A-l sequence corresponding to pAI-113 segregated with chromosome 11 as indicated at the
top of the panel. The intensity of this component in the several lanes correlated with the intensity of the LDH-A isozymes in
the hybrid lines and with the fraction of metaphases with human chromosome 11. A Hindlll digest of lambda DNA was used
for the size markers. The black marks below the chormosome segregation data indicate the gel lanes.
100
ARTERIOSCLEROSIS VOL 4, No 2, MARCH/APRIL 1984
Discussion
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Apolipoproteins have in common the requirement
that they bind and transport lipid in the blood stream.
Structurally the apolipoproteins that have been sequenced have all possessed amhipathic alpha-helical regions capable of interacting with aqueous and
nonpolar environments.1 In 1977 Barker and Dayhoff30, using amino-acid sequence data available
only for apo A-l, apo A-ll, apo C-l, and apo C-lll,
proposed that the apolipoproteins were all derived
from a common evolutionary precursor. The common function, structure, and perhaps even evolutionary background of the apolipoproteins suggests that
their genes comprise a multigene family. Families of
related DNA sequences have been described for the
globins, immunoglobulins, histocompatibility antigens, ribosomal proteins, myosin heavy chain, interferon, and other genes. Mapping of these families
revealed that some were widely dispersed in the
genome, whereas others, perhaps for functional reasons, have remained clustered.31 The assignment of
the apo A-l-apo C-lll gene complex to chromosome
11 raises the interesting question as to whether the
other apolipoprotein genes are also located in this
region of the genome. Although mapping with DNA
probes has not been done for the other apolipoprotein genes, there is some evidence from linkage
analysis, based on apolipoprotein electrophoretic
variants, that apo A-ll and apo E do not cosegregate
with apo A-l and may, in fact, be on different chromosomes. In the mouse, apo A-l has been linked to
other genes on chromosome 9, whereas apo A-ll is
linked to genes on chromosome 1. 32 In humans it
was observed that an electrophoretic variant of apo
A-l, apo A-l Marburg, did not cosegregate with apo E
electrophoretic variants in one informative family
studied.33 Another group has studied two families in
which polymorphic forms of apo E demonstrated
linkage with electrophoretic variants of the third component of complement in males.34 Since the latter
has been mapped to chromosome 1 d,35 apo E may
reside on this chromosome and therefore would not
be linked to the apo A-l-apo C-lll gene complex.
Thus, although two of the apolipoprotein genes, apo
A-l and apo C-lll, are closely linked in the genome, it
appears that at least some of the apolipoprotein
genes, apo A-ll and apo E, are dispersed. There is
currently no data on the chromosomal localization of
the other apolipoprotein genes.
In addition to the apo A-l-apo C-lll gene complex,
many other human genes have been mapped to
chromosome 11, including the cellular homologue of
the Harvey murine sarcoma-transforming gene,
LDH-A, lysosomal acid phosphatase ACP-2, the
non-alpha-globin gene complex, a locus for catalase, several cell surface antigen loci, insulin, collagenase, uroporphyrinogen I synthase (the enzyme
deficient in acute intermittant porphyria), and the
gene complex that predisposes to the aniridiaWilm's tumor syndrome36"59 (Figure 2). Commonly
occurring RFLPs have been described for several of
INS
c-ra8 H
NAG
WAGR, CAT "
LDHA
ACP-2
Apo Ai/cm
UPS
Figure 2. Schematic representation of the approximate
regionalizations of some of the loci assigned to human
chromosome 11. 36 ~ 60 These include: INS, insulin; WAGR,
Wilm's tumor-aniridia-genitourinary abnormality complex;
CAT, catalase; NAG, non-alpha globin complex; ACP-2,
lysosomal acid phosphatase, isozyme 2; c-rasH, cellular
homologue of the Harvey murine sarcoma transforming
gene; UPS, uroporphyrinogen I synthase; and apo A-l/CIII, the apolipoprotein A-l/C-lll gene complex (this report).
Additional loci assigned to this chromosome include a
number of cell surface antigens; cathepsin D; esterase 4;
and collagenase.
these loci. 60 " 64 It may be possible, using RFLPs in the
apo A-l-apo C-lll gene complex, through linkage
studies in large kindreds, to establish the relative
order and recombination distances between a number of these genes and the apo A-l-apo C-lll gene
complex.
Acknowledgments
We thank Stuart Orkin for providing the beta-globin probe and
Samuel Latt for helpful suggestions.
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ARTERIOSCLEROSIS VOL 4, No 2, MARCH/APRIL 1984
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• apo A-l • apo C-ll
gene mapping
Human apolipoprotein A-I--C-III gene complex is located on chromosome 11.
G A Bruns, S K Karathanasis and J L Breslow
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Arterioscler Thromb Vasc Biol. 1984;4:97-102
doi: 10.1161/01.ATV.4.2.97
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