Molecular Basis of Familial Hypertrophic 
Cardiomyopathy: Cardiac Myosin 
Heavy-Chain Gene Mutations 
Jonathan G. Seidman, Ph.D. — Investigator 
Dr. Seidman is also Professor of Genetics at Harvard Medical School. He received his undergraduate degree 
in biochemistry from Harvard University and his Ph.D. degree from the University of Wisconsin, where 
he studied with W. H. McClain. His postdoctoral studies were carried out in Philip Leder's laboratory at 
the National Institute of Child Health and Human Development. 
FAMILIAL hypertrophic cardiomyopathy 
(FHC) is a heart muscle disorder with an au- 
tosomal dominant pattern of inheritance. The 
disease is characterized clinically by myocardial 
hypertrophy, a wide spectrum of symptomatic in- 
volvement, and a 2-4 percent annual mortality 
rate from sudden death, which can occur without 
warning. Postmortem examination reveals in- 
creased myocardial mass with myocyte and myo- 
fibrillar disarray. Diagnosis is based on typical 
clinical features and the two-dimensional echo- 
cardiographic demonstration of unexplained left 
and/or right ventricular hypertrophy. In the 
young, diagnosis is often complicated, because 
hypertrophy may not develop until after adoles- 
cent growth has been completed. The anatomical 
distribution of myocardial hypertrophy and sever- 
ity of symptoms may be quite variable, even 
within a family. 
During the past 30 years, the cardiac features of 
FHC have been extensively reported, but the eti- 
ology and molecular pathophysiology have re- 
mained speculative. Last year we reported the lo- 
calization of a gene on chromosome 1 4 that can 
be mutated to cause FHC. During the past year we 
have demonstrated that this is the cardiac myosin 
heavy-chain gene(s). 
Chromosomal localization of the disease locus 
suggested candidate genes that might be responsi- 
ble for FHC. In particular, cardiac myosin heavy- 
chain genes (a and |8) are located on chromo- 
some 14 band qll-13. During the past year we 
defined the structure of these genes in affected 
individuals from two unrelated families (A and 
B). Affected members of family A have a point 
mutation in exon 1 3 of their gene that changes 
an arginine residue to a glutamine residue. Be- 
cause this arginine residue is highly conserved 
during evolution and because no normal individ- 
uals have this mutation, we suggested that this 
point mutation is responsible for the disease in 
affected members of this family. 
Affected members of family B have an unusual 
cardiac myosin heavy-chain gene in their ge- 
nomes. These individuals have a third cardiac 
myosin heavy-chain gene on one chromosome. 
This third gene is a hybrid derived from exons 
1-27 of the a gene, and the remainder of the 
gene is derived from the /3 gene. This hybrid gene 
is not found in the genomes of unaffected individ- 
uals. From these studies we conclude that muta- 
tion of these genes can cause FHC. 
We have also demonstrated that FHC is a geneti- 
cally heterogeneous disorder, by studying the in- 
heritance of FHC in two other unrelated families 
(C and D). In these families the disease is not 
genetically linked to the cardiac myosin heavy- 
chain genes on chromosome 1 4 . We propose that 
their disease is due to defects in other genes that 
encode products that either affect the expression 
of cardiac myosin heavy chains or that interact 
with cardiac myosin heavy-chain genes to pro- 
duce functional cardiac muscle. We hope that 
these studies will lead to a better understanding 
of how cardiac muscle functions and how defects 
in cardiac muscle proteins lead to the clinical 
symptoms found in FHC patients. 
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