A, and Abd-B, the POU domain genes become dere- 
pressed in the abdominal segments of the ventral 
nervous system. Similarly, the expression patterns in 
the peripheral nervous system of the abdominal seg- 
ments transform to that of thoracic segments. There- 
fore these POU domain genes behave as downstream 
genes of the homeotic gene functions. An immediate 
goal is to determine if this regulation is carried out 
directly by the homeotic proteins. 
The second method used to isolate candidate 
downstream genes was the enhancer-trap screen. In 
this method a transposon carrying a promoter and a 
reporter gene is inserted randomly around the ge- 
nome to identify cis-regulatory elements that re- 
spond to homeotic gene activities. A number of can- 
didate genes from this screen are being analyzed. 
One insertion, which has been shown to map at a 
gene called dachsous, displays a strong dachsous 
phenotype when in trans over existing dachsous al- 
leles. This gene, which has been cloned and se- 
quenced (in Dr. Corey Goodman's laboratory 
[HHMI, University of California, Berkeley]) encodes 
a large, transmembrane protein containing cadherin 
repeats. 
Dr. Sakonju is also Assistant Professor of Hu- 
man Genetics at the University of Utah School of 
Medicine. 
Articles 
Cumberledge, S., Szabad, J., and Sakonju, S. 1992. 
Gonad formation and development requires the 
abd-A domain of the bithorax complex in Dro- 
sophila melanogaster. Development 115:395- 
402. 
Lloyd, A., and Sakonju, S. 1991. Characterization 
of two Drosophila POU domain genes, related to 
oct-1 and oct-2, and the regulation of their ex- 
pression patterns. Mech Dev 36:87-102. 
CARDIAC MYOSIN MUTATIONS AND HYPERTROPHIC CARDIOMYOPATHY 
Jonathan G. Seidman, Ph.D., Investigator 
Familial hypertrophic cardiomyopathy (FHC) is 
an autosomal dominant disorder characterized by 
unexplained myocardial hypertrophy. The clinical 
presentation is quite variable but can include syn- 
cope, arrhythmias, congestive heart failure, and sud- 
den death. Diagnosis in young people is particularly 
important, as the incidence of sudden death appears 
higher in this group and may be the presenting 
symptom. Indeed, in many series, hypertrophic car- 
diomyopathy is one of the most common autopsy 
findings among young athletes who die suddenly. 
Most of these were undiagnosed previously. Diagno- 
sis in this age group may be particularly difficult, 
since the diagnostic clinical and echocardiographic 
criteria may not be manifest until adulthood. 
Because mutations in the cardiac myosin heavy- 
chain (MHC) genes were implicated as the cause of 
FHC in two families, these genes were analyzed in 
affected persons from other families. During the 
past year Dr. Seidman and his colleagues made con- 
siderable efforts to find the cardiac MHC mutations 
that cause FHC in more than 30 unrelated families. 
The laboratory first demonstrated that most FHC 
mutations are missense or point mutations in the 
MHC genes. A variety of techniques have been suc- 
cessfully employed in the detection of missense mu- 
tations within genes. Most of these are based on am- 
plification of genomic DNA sequences and analyses 
of individual exons. Application of these ap- 
proaches to the study of FHC mutations was more 
difficult because the /3-MHC polypeptide is encoded 
in 40 exons, and hence 40 independent analyses are 
required to examine the entire gene. Furthermore, 
FHC is an autosomal dominant disorder and affected 
individuals are heterozygous, bearing one mutated 
and one normal gene. Genomic analyses may fail to 
detect deletions of entire exons or mutations that 
alter gene splicing because of the presence of one 
normal gene. Access to messenger RNA (mRNA) in 
which intronic sequences have been excised would 
overcome these limitations and allow analysis of 
coding regions in a more rapid and convenient 
manner. 
Although MHC mRNAs are abundant in the heart, 
expression elsewhere is low, and restricted to se- 
lected fibers in slow-twitch skeletal muscle. Normal 
and mutant jS-MHC sequences were detected in RNA 
transcripts from peripheral lymphocytes and 
Epstein-Barr virus-transformed lymphocyte cell 
lines. This finding permitted examination of /3- 
cardiac MHC mRNA, even though cardiac tissue was 
not available. (These studies were supported in part 
by a grant from the National Institutes of Health.) 
In the first study, seven different jS-cardiac MHC 
mutations were found among 24 unrelated FHC pro- 
bands. Four mutations were identified in two or 
GENETICS 257 
