Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease.

Solomon, S D; Jarcho, J A; McKenna, William J.; Geisterfer-Lowrance, Anja; Germain, Ronald N.; Salerni, Rosemarie; Seidman, J. G.; Seidman, C E

doi:10.1172/jci114802

Cited by 141 publications

(36 citation statements)

References 16 publications

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“…These have all been detected in the head and head-rod junction regions of the f3-MHC protein. The f-MHC gene, however, has been excluded as the disease locus in other kindreds (3,9,10).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Cuda

Fananapazir²,

Zhu³

et al. 1993

J. Clin. Invest.

227

128

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“…These have all been detected in the head and head-rod junction regions of the f3-MHC protein. The f-MHC gene, however, has been excluded as the disease locus in other kindreds (3,9,10).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Cuda

Fananapazir²,

Zhu³

et al. 1993

J. Clin. Invest.

227

128

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“…HCM represents a paradigm ofcardiac pathophysiology and elucidation of its molecular basis should provide information fundamental to our understanding of the biology and pathology of the myocardium. The gene responsible for FHCM has been localized in some families to chromosome 14 (3)(4)(5)(6), and the f3-myosin heavy chain (i3MHC) gene has been identified as the candidate gene for this disease (3)(4)(5). Three mutations in #MHC gene in two families with FHCM have been described.…”

Section: Introductionmentioning

confidence: 99%

Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.

Marian¹,

Yu²,

Mares³

et al. 1992

J. Clin. Invest.

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Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease affecting primarily the myocardium. The gene responsible for FHCM has been localized to chromosome 14 in some families and several mutations have been described in the #-myosin heavy chain (ftMHC), a candidate gene for the disease. We recently identified a family with HCM in whom we did not detect any of the known mutations in the ftMHC gene (the a/i#MHC hybrid gene and the missense mutation in exons 13 and 9). However, we did observe a novel 9.5-kb BamHI restriction fragment length polymorphism detected by a ,6MHC probe on Southern blots of DNA from the proband of this family. Similarly, a novel 3.8-kb TaqI polymorphism and a novel 4.3-kb HindI1 polymorphism were detected on Southern blots of DNA from the same proband. Polymerase chain reaction (PCR) was used to amplify the segment of the ,MHC that was detected by pSC14 probe. PCR amplification of the distal 3'-end of the i6MHC gene yielded an additional product in the DNA template from the proband which was subsequently cloned and sequenced. The sequence analysis showed a 2.4-kb nucleotide deletion involving one allele of the ,6MHC gene. The deletion includes part of the intron 39, exon 40 including the 3'-untranslated region and the polyadenylation signal, and part of the fl-aMHC intergenic region. This deletion was inherited in Mendelian fashion in an additional three members of this small family of which only the proband has developed clinically diagnosed HCM at a very late onset (age 59 yr), the other three family members are younger and have not developed the disease at the ages of 10, 32, and 33 yr. (J. Clin. Invest. 1992.

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“…'-" In some kindreds, the disease has been linked to the f-myosin heavy chain (3-MHC) gene locus on chromosome 14ql. [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] In these kindreds, HCM has been associated with substitutions of single highly conserved amino acids in the head or head-rod junction of the ,B-MHC molecule. We have previously reported that clinical expression has differed significantly in two kindreds with distinct 3-IMHC gene mutations: The 908``u va1 mutation has been associated with low disease penetrance and a benign prognosis.…”

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confidence: 99%

Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations.

1994

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BACKGROUND We have previously described two distinct mutations in the beta-myosin heavy chain gene with markedly different clinical presentations and outcome: The 908Leu-->Val mutation was associated with a low disease penetrance and a benign prognosis. In contrast, the 403Arg-->Gln mutation in a Caucasian kindred was associated with a 100% disease penetrance and high incidence of sudden cardiac death. Recently, another mutation, 606Val-->Met, has been reported to be associated with "near normal survival" and offered as evidence for the benign nature of neutral charge substitutions. METHODS AND RESULTS We report (1) a large kindred (245 family members at risk of inheriting the disease gene) with a 256Gly-->Glu mutation characterized by a similar disease penetrance in adults and in children (56% and 60%, respectively) and a cumulative sudden cardiac death rate of only 2% at 50 years of age, (2) a kindred with the 606Val-->Met mutation with four sudden cardiac deaths in eight affected individuals, and (3) a Korean kindred with the 403Arg-->Gln mutation. Although the disease occurred early and was associated with a high prevalence of myocardial ischemia in both of our kindreds with the 403Arg-->Gln mutation, no sudden cardiac death or syncope has occurred in the Korean kindred. Furthermore, in the Caucasian kindred, all patients had nonobstructive hypertrophic cardiomyopathy, but most of the patients in the Korean kindred had left ventricular outflow obstruction. CONCLUSIONS The conclusions are as follows: (1) Although several sudden cardiac deaths are sufficient to establish that a mutation is malignant, study of a large kindred is necessary to be certain that a mutation is benign. To date, only the 908Leu-->Val and the 256Gly-->Glu mutations satisfy this requirement. (2) The 256Gly-->Glu mutation demonstrates that not all mutations that result in a charge change are malignant. (3) Conversely, the 606Val-->Met mutation is malignant in some kindreds; hence, despite the absence of a charge change, minor substitutions in critical regions of beta-myosin heavy chain protein may also have serious consequences. (4) The diverse ethnic origins of the two 403Arg-->Gln kindreds provide evidence suggesting that the identical mutation occurred independently and was associated with different genetic backgrounds. Their distinct phenotypes underline the importance of modifying genes and nongenetic factors.

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Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease.

Cited by 141 publications

References 16 publications

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Detection of a new mutation in the beta-myosin heavy chain gene in an individual with hypertrophic cardiomyopathy.

Genotype-phenotype correlations in hypertrophic cardiomyopathy. Insights provided by comparisons of kindreds with distinct and identical beta-myosin heavy chain gene mutations.

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