DNA LINKAGE--A GENE(S) RESPONSIBLE FOR FAMILIAL DILATED CARDIOMYOPATHY

  • Roberts, Robert F. (PI)
  • Roberts, Robert (PI)
  • Roberts, Robert (PI)
  • CASKEY, THOMAS (PI)
  • SCHNEIDER, MICHAEL (PI)
  • MANN, DOUGLAS LOWELL (PI)
  • Schwartz, Robert (PI)
  • MICHAEL, LLOYD (PI)
  • QUINONES, MIGUEL (PI)
  • FRENCH, BRENT (PI)

Project: Research project

Project Details

Description

Hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young
adults. Most cases are believed to be the result of an autosomal dominant
inherited trait. Salient features of the cardiac pathology include
increased muscle mass with fiber disorganization and myofibrillar disarray
of the affected myocardium which consistently involves the interventricular
septum. The free ventricular wall may also be involved in up to 30% of
cases. This project seeks to characterize the defective cellular
structures, their proteins and genes involved in the disarray and
disorganization of the myocardium in familial cases of HCM. Biopsy
material from the left septum and left ventricular free wall will be
obtained from catheterization of HCM patients with documented familial
occurrence, non-HCM cardiac patients, and from explanted hearts of non-HCM
patients with a spectrum of cardiomyopathies. Myofibrils and Z-discs will
be prepared from glycerinated myocardial fibers. Immunocytochemistry of
membrane-cytoskeletal proteins including alpha-actinin, desmin, spectrin
and sarcoplasmic reticulum Ca++-ATPase will be performed in order to
determine the subcellular location of the defect. One- and two-dimensional
electrophoresis and immunoblotting of proteins from myofibrillar and non-
myofibrillar fractions and from Z-disc and 0.6 M KI-extractable fractions
will be analyzed for alterations in molecular weight, change, and content.
Specific antibodies will be used to screen a lambda gt11 expression library
of human cardiac cDNAs, if the gene for the altered protein or closely
related isoform is not already cloned or sequenced. The cloned gene or
synthetic oligonucleotide will be used in concurrent genomic studies to
uncover the DNA sequence alteration. The antibody and DNA probes will
ultimately be used to study the pathogenesis of myocardial disarray and
dysfunction in familial HCM.
StatusFinished
Effective start/end date10/1/9612/31/97

Funding

  • National Heart, Lung, and Blood Institute

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