Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy

Rocio Ortiz-Lopez, Hua Li, Jason Su, Veronica Goytia, Jeffrey Towbin

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

Background: X-linked dilated cardiomyopathy (XLCM) has previously been shown to be due to mutations in the dystrophin gene which is located at Xp21. Mutations in the 5' portion of the gene, including the muscle promoter, exon 1, and the exon 1-intron 1 splice site, have been reported previously. The purpose of this study was to analyze the originally described family with XLCM (and others) for dystrophin mutations. Methods and Results: Polymerase chain reaction (PCR) was used to amplify genomic DNA, and reverse- transcriptase PCR amplified cDNA from RNA obtained from heart and lymphoblastoid cell lines. Primers to the muscle promoter, brain promoter, and Purkinje cell promoter were designed, in addition to the exon I to exon 14 regions of dystrophin. Single-strand conformation polymorphism analysis was used for mutation detection, and DNA sequencing defined the mutation. Protein modeling was used for amino acid and secondary structure analysis. A missense mutation in exon 9 at nucleotide 1043 was identified that causes an alanine to be substituted for threonine, a highly conserved amino acid, at position 279 (T279A). This mutation results in a change in polarity in the evolutionarily conserved first hinge region (HI) of the protein and substitution of a β-sheet for α-helix in this portion of the protein, destabilizing the protein. Conclusions: A novel missense mutation in exon 9 of dystrophin causing an abnormality at HI leads to the cardiospecific phenotype of XLCM.

Original languageEnglish (US)
Pages (from-to)2434-2440
Number of pages7
JournalCirculation
Volume95
Issue number10
DOIs
StatePublished - Jan 1 1997
Externally publishedYes

Fingerprint

Dystrophin
Missense Mutation
Exons
Mutation
Proteins
Imino Acids
Muscles
Purkinje Cells
Threonine
Reverse Transcriptase Polymerase Chain Reaction
DNA Sequence Analysis
Alanine
Introns
Genes
Dmd-Associated Dilated Cardiomyopathy
Nucleotides
Complementary DNA
RNA
Phenotype
Amino Acids

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. / Ortiz-Lopez, Rocio; Li, Hua; Su, Jason; Goytia, Veronica; Towbin, Jeffrey.

In: Circulation, Vol. 95, No. 10, 01.01.1997, p. 2434-2440.

Research output: Contribution to journalArticle

Ortiz-Lopez, Rocio ; Li, Hua ; Su, Jason ; Goytia, Veronica ; Towbin, Jeffrey. / Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. In: Circulation. 1997 ; Vol. 95, No. 10. pp. 2434-2440.
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abstract = "Background: X-linked dilated cardiomyopathy (XLCM) has previously been shown to be due to mutations in the dystrophin gene which is located at Xp21. Mutations in the 5' portion of the gene, including the muscle promoter, exon 1, and the exon 1-intron 1 splice site, have been reported previously. The purpose of this study was to analyze the originally described family with XLCM (and others) for dystrophin mutations. Methods and Results: Polymerase chain reaction (PCR) was used to amplify genomic DNA, and reverse- transcriptase PCR amplified cDNA from RNA obtained from heart and lymphoblastoid cell lines. Primers to the muscle promoter, brain promoter, and Purkinje cell promoter were designed, in addition to the exon I to exon 14 regions of dystrophin. Single-strand conformation polymorphism analysis was used for mutation detection, and DNA sequencing defined the mutation. Protein modeling was used for amino acid and secondary structure analysis. A missense mutation in exon 9 at nucleotide 1043 was identified that causes an alanine to be substituted for threonine, a highly conserved amino acid, at position 279 (T279A). This mutation results in a change in polarity in the evolutionarily conserved first hinge region (HI) of the protein and substitution of a β-sheet for α-helix in this portion of the protein, destabilizing the protein. Conclusions: A novel missense mutation in exon 9 of dystrophin causing an abnormality at HI leads to the cardiospecific phenotype of XLCM.",
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N2 - Background: X-linked dilated cardiomyopathy (XLCM) has previously been shown to be due to mutations in the dystrophin gene which is located at Xp21. Mutations in the 5' portion of the gene, including the muscle promoter, exon 1, and the exon 1-intron 1 splice site, have been reported previously. The purpose of this study was to analyze the originally described family with XLCM (and others) for dystrophin mutations. Methods and Results: Polymerase chain reaction (PCR) was used to amplify genomic DNA, and reverse- transcriptase PCR amplified cDNA from RNA obtained from heart and lymphoblastoid cell lines. Primers to the muscle promoter, brain promoter, and Purkinje cell promoter were designed, in addition to the exon I to exon 14 regions of dystrophin. Single-strand conformation polymorphism analysis was used for mutation detection, and DNA sequencing defined the mutation. Protein modeling was used for amino acid and secondary structure analysis. A missense mutation in exon 9 at nucleotide 1043 was identified that causes an alanine to be substituted for threonine, a highly conserved amino acid, at position 279 (T279A). This mutation results in a change in polarity in the evolutionarily conserved first hinge region (HI) of the protein and substitution of a β-sheet for α-helix in this portion of the protein, destabilizing the protein. Conclusions: A novel missense mutation in exon 9 of dystrophin causing an abnormality at HI leads to the cardiospecific phenotype of XLCM.

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