X-linked dilated cardiomyopathy

Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus

Jeffrey Towbin, J. F. Hejtmancik, P. Brink, B. Gelb, Min Zhu Xue Min Zhu, J. S. Chamberlain, E. R.B. McCabe, M. Swift

Research output: Contribution to journalArticle

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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, θ=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.

Original languageEnglish (US)
Pages (from-to)1854-1865
Number of pages12
JournalCirculation
Volume87
Issue number6
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

Fingerprint

Dystrophin
Genetic Linkage
Duchenne Muscular Dystrophy
Molecular Biology
Cardiomyopathies
Genes
Multiplex Polymerase Chain Reaction
Pedigree
Western Blotting
Genetic Techniques
X-Linked Genes
Antibodies
Sequence Deletion
X Chromosome
Dmd-Associated Dilated Cardiomyopathy
Genetic Markers
Point Mutation
Myocardium
Skeletal Muscle
Proteins

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

X-linked dilated cardiomyopathy : Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. / Towbin, Jeffrey; Hejtmancik, J. F.; Brink, P.; Gelb, B.; Xue Min Zhu, Min Zhu; Chamberlain, J. S.; McCabe, E. R.B.; Swift, M.

In: Circulation, Vol. 87, No. 6, 01.01.1993, p. 1854-1865.

Research output: Contribution to journalArticle

Towbin, J, Hejtmancik, JF, Brink, P, Gelb, B, Xue Min Zhu, MZ, Chamberlain, JS, McCabe, ERB & Swift, M 1993, 'X-linked dilated cardiomyopathy: Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus', Circulation, vol. 87, no. 6, pp. 1854-1865. https://doi.org/10.1161/01.CIR.87.6.1854
Towbin, Jeffrey ; Hejtmancik, J. F. ; Brink, P. ; Gelb, B. ; Xue Min Zhu, Min Zhu ; Chamberlain, J. S. ; McCabe, E. R.B. ; Swift, M. / X-linked dilated cardiomyopathy : Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. In: Circulation. 1993 ; Vol. 87, No. 6. pp. 1854-1865.
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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, θ=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.",
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T2 - Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus

AU - Towbin, Jeffrey

AU - Hejtmancik, J. F.

AU - Brink, P.

AU - Gelb, B.

AU - Xue Min Zhu, Min Zhu

AU - Chamberlain, J. S.

AU - McCabe, E. R.B.

AU - Swift, M.

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Y1 - 1993/1/1

N2 - 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, θ=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.

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