X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus - PubMed (original) (raw)

X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus

J A Towbin et al. Circulation. 1993 Jun.

Abstract

Background: X-linked cardiomyopathy (XLCM) is a rapidly progressive primary myocardial disorder presenting in teenage males as congestive heart failure. Manifesting female carriers have later onset (fifth decade) and slower progression. The purpose of this study was to localize the 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 calculated using the LINKAGE computer program package. Deletion analysis included multiplex polymerase chain reaction (PCR). Dystrophin protein was evaluated by Western blotting with N-terminal and C-terminal dystrophin antibody. Linkage of XLCM to the centromeric portion of the dystrophin or Duchenne muscular dystrophy (DMD) locus at Xp21 was demonstrated 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 proximal DMD genomic and cDNA probes and polymerase chain reaction polymorphisms supported linkage. No deletions were observed. Abnormalities of cardiac dystrophin were shown by Western blotting with N-terminal dystrophin antibody, whereas skeletal muscle dystrophin was normal, suggesting primary involvement of the DMD gene with preferential involvement of cardiac muscle.

Conclusions: XLCM is due to an abnormality within the centromeric half of the dystrophin genomic region in heart. This 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 tissue, 3) splicing abnormalities, resulting in an abnormal cardiac protein, or 4) deletion mutations undetectable by Southern and multiplex polymerase chain reaction analysis.

PubMed Disclaimer

Cited by

Molecular Aspects of Myocarditis.
Bowles NE, Towbin JA. Bowles NE, et al. Curr Infect Dis Rep. 2000 Aug;2(4):308-314. doi: 10.1007/s11908-000-0008-x. Curr Infect Dis Rep. 2000. PMID: 11095870
Novel Therapies for Prevention and Early Treatment of Cardiomyopathies.
Repetti GG, Toepfer CN, Seidman JG, Seidman CE. Repetti GG, et al. Circ Res. 2019 May 24;124(11):1536-1550. doi: 10.1161/CIRCRESAHA.119.313569. Circ Res. 2019. PMID: 31120825 Free PMC article. Review.
Disruption of striated preferentially expressed gene locus leads to dilated cardiomyopathy in mice.
Liu X, Ramjiganesh T, Chen YH, Chung SW, Hall SR, Schissel SL, Padera RF Jr, Liao R, Ackerman KG, Kajstura J, Leri A, Anversa P, Yet SF, Layne MD, Perrella MA. Liu X, et al. Circulation. 2009 Jan 20;119(2):261-8. doi: 10.1161/CIRCULATIONAHA.108.799536. Epub 2008 Dec 31. Circulation. 2009. PMID: 19118250 Free PMC article.
Age-dependent dystrophin loss and genetic reconstitution establish a molecular link between dystrophin and heart performance during aging.
Townsend D, Daly M, Chamberlain JS, Metzger JM. Townsend D, et al. Mol Ther. 2011 Oct;19(10):1821-5. doi: 10.1038/mt.2011.120. Epub 2011 Jul 5. Mol Ther. 2011. PMID: 21730971 Free PMC article.
[Classification of cardiomyopathies according to the WHO/ISFC Task Force--more questions than answers?].
Maisch B. Maisch B. Med Klin (Munich). 1998 Apr 15;93(4):199-209. doi: 10.1007/BF03044794. Med Klin (Munich). 1998. PMID: 9594528 German.

X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus - PubMed (original) (raw)