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CLINICAL STUDY: HEART FAILURE

Comprehensive mutation scanning of the dystrophin gene in patients with nonsyndromic X-linked dilated cardiomyopathy

Jinong Feng, MD^*, Jin Yan, MD^*, Carolyn H. Buzin, PhD^*, Steve S. Sommer, MD, PhD^*,* and Jeffrey A. Towbin, MD

^* Department of Molecular Genetics, City of Hope National Medical Center/Beckman Research Institute, Duarte, California, USA
Department of Pediatrics (Cardiology) and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA

Manuscript received January 11, 2002; revised manuscript received June 10, 2002, accepted June 24, 2002.

^* Reprint requests and correspondence: Dr. Steve S. Sommer, Departments of Molecular Genetics and Molecular Diagnosis, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, California 91010-3000, USA.
sommerlab{at}coh.org

OBJECTIVES: The goal of this study was to perform comprehensive mutation analysis of the dystrophin gene in patients with X-linked dilated cardiomyopathy (XLCM).

BACKGROUND: X-linked dilated cardiomyopathy is a familial disease that is characterized by congestive heart failure without clinical signs of skeletal myopathy. Mutations in the dystrophin gene have been associated with the X-linked form of dilated cardiomyopathy. However, the fraction of XLCM with dystrophin mutations and the distribution of those mutations is not clear. Technical difficulties previously limited comprehensive mutation analysis of this very large gene.

METHODS: The Detection Of Virtually All Mutations-Single Strand Conformation Polymorphism (SSCP) (DOVAM-S), a robotically enhanced multiplexed scanning method that is a highly sensitive modification of SSCP, has successfully detected all of 240 mutations and polymorphisms in three blinded analyses of the factor VIII, factor IX, and ATM genes. Utilizing this method all 79 coding exons and splice junctions for the muscle dystrophin gene, along with six alternative exon 1 sequences, were scanned in eight patients with XLCM.

RESULTS: This is the first comprehensive scanning of the dystrophin gene in XLCM. Three of eight patients have putative mutations, including two splicing mutations and a missense mutation at a highly conserved amino acid.

CONCLUSIONS: Mutations within the coding regions and splice junctions in the dystrophin gene only account for some cases of XLCM. Genetic heterogeneity and/or undetected mutations in auxiliary regulatory regions or deep within introns may occur in XLCM.

Abbreviations and Acronyms   BMD   Becker muscular dystrophy   CK-MM   creatine kinase-all muscle isoform   DCM   dilated cardiomyopathy   DOVAM-S   Detection Of Virtually All Mutations-Single Strand Conformation Polymorphism   EDMD   Emery-Dreifuss muscular dystrophy   PCR   polymerase chain reaction   XLCM   X-linked dilated cardiomyopathy

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