X-LINKED DILATED CARDIOMYOPATHY - MOLECULAR-GENETIC EVIDENCE OF LINKAGE TO THE DUCHENNE MUSCULAR-DYSTROPHY (DYSTROPHIN) GENE AT THE XP21 LOCUS

Background. X-linked cardiomyopathy (XLCM) is a rapidly progressive pr imary myocardial disorder presenting in teenage males as congestive he art failure. Manifesting female carriers have later onset (fifth decad e) and slower progression. The purpose of this study was to localize t he XLCM gene locus in two families using molecular genetic techniques. Methods and Results. Linkage analysis using 60 X-chromosome-specific DNA markers was performed in a previously reported large XLCM pedigree and a smaller new pedigree. Two-point and multipoint linkage was calc ulated using the LINKAGE computer program package. Deletion analysis i ncluded multiplex polymerase chain reaction (PCR). Dystrophin protein was evaluated by Western blotting with N-terminal and C-terminal dystr ophin antibody. Linkage of XLCM to the centromeric portion of the dyst rophin or Duchenne muscular dystrophy (DMD) locus at Xp21 was demonstr ated with combined maximum logarithm of the scores of +4.33, theta = 0 with probe XJ1.1 (DXS206) using two-point linkage and +4.81 at XJ1.1 with multipoint linkage analysis. LOD scores calculated using other pr oximal DMD genomic and cDNA probes and polymerase chain reaction polym orphisms supported linkage. No deletions were observed. Abnormalities of cardiac dystrophin were shown by Western blotting with N-terminal d ystrophin antibody, whereas skeletal muscle dystrophin was normal, sug gesting primary involvement of the DMD gene with preferential involvem ent of cardiac muscle. Conclusions. XLCM is due to an abnormality with in the centromeric half of the dystrophin genomic region in heart. Thi s abnormality could be due to 1) a point mutation in the 5' region of the DMD coding sequence preferentially affecting cardiac function, 2) a cardiac-specific promoter mutation that alters expression in this ti ssue, 3) splicing abnormalities, resulting in an abnormal cardiac prot ein, or 4) deletion mutations undetectable by Southern and multiplex p olymerase chain reaction analysis.