MOLECULAR BASIS OF FAMILLU. HYPERTROPHIC CARDIOMYOPATHY 
AND INSULIN-DEPENDENT DIABETES 
Jonathan G. Seidman, Ph.D., Investigator 
I. The Locus Encoding the Familial Hypertrophic 
Cardiomyopathy Gene Maps to Chromosome I4ql. 
Familial hypertrophic cardiomyopathy (HC) is an 
idiopathic heart muscle disorder with an autosomal 
dominant pattern of inheritance. The disease is 
characterized clinically by myocardial hypertrophy, 
a wide spectrum of symptomatic involvement, and 
a 2-4% annual mortality rate from sudden death, 
which can even occur in the asymptomatic individ- 
ual. Postmortem examination reveals increased 
myocardial mass with myocyte and myofibrillar dis- 
array. Diagnosis is based on typical clinical features 
and the two-dimensional echocardiographic dem- 
onstration of unexplained left and/or right ventricu- 
lar hypertrophy. Diagnosis is often complicated in 
the young because hypertrophy may not develop 
until after adolescent grov^h has been completed. 
The anatomical distribution of myocardial hypertro- 
phy and severity of symptoms may be variable, even 
within a family. During the past 30 years the cardiac 
features of this disease have been extensively re- 
ported, but the etiology and molecular pathophysi- 
ology have remained speculative. 
To understand the genetic basis for familial HC, 
Dr. Seidman used a molecular genetic technique to 
identify the chromosomal position of the disease 
locus in a large family. This approach has been used 
by others to identify the genetic loci responsible 
for more than 30 inherited disorders, including 
Huntington's disease, familial polyposis, cutane- 
ous malignant melanoma-dysplastic nevus syn- 
drome, ataxia-telangiectasia, and Duchenne mus- 
cular dystrophy. Cosegregation analysis, which 
defines genetic linkage between a known chromo- 
somal location (defined by a DNA probe) and the 
disease gene, has been used to map each disease 
locus to a region of the human genome. Because 
there were neither candidate genes nor cytogenetic 
abnormalities to suggest the chromosomal lo- 
cation of the gene responsible for familial HC, 
Dr. Seidman and his colleagues began to screen 
DNA probes corresponding to loci throughout 
the genome, to identify one that is linked to the 
familial HC locus. These DNA probes recognize re- 
striction fragment length polymorphisms (RFLPs) 
and are a subset of DNA markers used to construct 
a genetic linkage map reported to span the human 
genome. 
A large family in which the familial HC gene seg- 
regated as an autosomal dominant trait was clini- 
cally evaluated and used in genetic analyses. Forty- 
one polymorphic DNA probes were used before 
identifying one (CRI-L436, derived from chromo- 
some 14) that is closely linked to the familial HC 
locus in this family. No instances of recombination 
between the familial HC locus and the D14S26 
locus (defined by CRI-L436) were observed. Statisti- 
cal analysis of the disease status and CRI-L436 al- 
leles in 41 unaffected members and 20 affected 
members of this family suggests that the odds are 
> 2,000,000,000:1 (lod score = +937 at J = 0) that 
the familial HC gene locus is genetically linked to 
D14S26. 
Chromosomal location of the disease locus sug- 
gests candidate genes that may be responsible for 
familial HC and provides a basis for determining 
whether additional genetic loci can independently 
cause this disorder in unrelated families. 
II. Autoimmunity in Non-Obese Diabetic Mice 
Bearing a Functional T Cell Receptor (3-Chain 
Transgene. 
The NOD (non-obese diabetic) mouse develops 
spontaneous insulin-dependent diabetes mellitus 
characterized by infiltration of mononuclear cells, 
around and into the pancreatic islets, followed by 
beta cell destruction, similar to human type I diabe- 
tes. Diabetes susceptibility is associated with at 
least three recessive genes, one of which maps to 
the class II region of the major histocompatibility 
complex (MHC) . There is a large body of evidence 
indicating that type I diabetes in animal models is 
T cell mediated. T cells predominate in the insulitis 
lesion, and diabetes can be prevented in NOD mice 
with therapies directed against T cells, such as neo- 
natal thymectomy and the introduction of the 
nu/nu gene, which produces profound T cell im- 
munodeficiency. Furthermore, overt disease can be 
adoptively transferred into healthy NOD neonates 
and preirradiated adult male recipients using puri- 
fied T cells from diabetic mice. Disease can be 
transferred by islet-specific T cell lines. Evidence for 
T cell involvement in disease pathogenesis along 
with the selective nature of beta cell destruction 
has led to speculation that specific T cell receptor 
(TCR) sequences may be important for lymphocyte 
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