Familial Hypertrophic Cardiomyopathy Associated with a Novel Missense Mutation Affecting the ATP-binding Region of the Cardiac Beta-myosin Heavy Chain (original) (raw)
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Proceedings of the National Academy of Sciences, 1995
In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caused by > 29 missense mutations in the cardiac beta-myosin heavy chain (MYH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional structure of the chicken skeletal muscle myosin head have provided the opportunity to examine the structural consequences of these naturally occurring mutations in human beta-cardiac myosin. This study demonstrates that the mutations are related to distinct structural and functional domains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locations of these m...
Journal of Clinical Investigation, 1996
More than 30 missense mutations in the beta-cardiac myosin heavy chain gene have been shown to be responsible for familial hypertrophic cardiomyopathy. To clarify the effects of these point mutations on myosin motor function, we expressed wild-type and mutant human beta-cardiac myosin heavy chains in insect cells with human cardiac light chains. The wild-type myosin was well purified with similar enzymatic and motor activities to those of the naturally isolated V3 cardiac myosin. Arg249-->Gln and Arg453-->Cys mutations resulted in decreased actin translocating activity (61 and 23% of the wild-type, respectively) with decreased intrinsic ATPase activity. Arg403-->Gln mutation greatly decreased actin translocating activity (27% of wild type) with a 3.3-fold increased dissociation constant for actin, while intrinsic ATPase activity was unchanged. Val606-->Met mutation only mildly affected the actin translocating activity as well as ATPase activity of myosin. The degree of deterioration by each mutation was closely correlated with the prognosis of the affected kindreds, indicating that myosin dysfunction caused by the point mutations is responsible for the pathogenesis of the disease. Structure/function relationship of myosin is discussed.
Cytogenetic and Genome Research, 1990
The genes coding for each human cardiac myosin heavy chain (a-MHC and B-MHC, MYH6 and MYH7, respectively) are tightly linked and the o-MHC gene has been assigned to chromosome 14. In order to provide a more precise regional local-ization, in situ hybridizationexperiments were carried out using a sHlabeled probe derived from a p-MHC genomic clone. The results demonstrated that the human cardiac MHC genes are located within the ql2 band of chromosome 14.
Missense mutation of the β-cardiac myosin heavy-chain gene in hypertrophic cardiomyopathy
American Journal of Medical Genetics, 1995
Hypertrophic cardiomyopathy occurs as an autosomal dominant familial disorder or as a sporadic disease without familial involvement. We describe a missense mutation of the p-cardiac myosin heavy chain (MHC) gene, a G to T transversion (741 Gly-+Trp) identified by direct sequencing of exon 20 in four individuals affected with familial hypertrophic cardiomyopathy. Three individuals with sporadic hypertrophic cardiomyopathy, whose parents are clinically and genetically unaffected, had sequence variations of exon 34 of the a-cardiac MHC gene (a C to T transversion, 1658 Asp+Asp, resulting in FokI site polymorphism), of intron 33 of the a-cardiac MHC gene (a G to A and an A to T transversion), and also of intron 14 of the p-cardiac MHC gene (a C to T transversion in a patient with Noonan syndrome). Including our case, 30 missense mutations of the p-cardiac MHC gene in 49 families have been reported thus far worldwide. Almost all are located in the region of the gene coding for the globular head of the molecule, and only one mutation was found in both Caucasian and Japanese families. Missense mutations of the p-cardiac MHC gene in hypertrophic cardiomyopathy may therefore differ according to race.
Journal of Clinical Investigation, 1993
Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14qll-ql2, encodes the #myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the #-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14qll-ql2. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403 '" and 403ig-TriP in families 720 and 730, respectively. The 403ArgI' mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403 r"T'P mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the #-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the j-myosin heavy chain gene is a
FEBS Letters, 2000
The heart disease familial hypertrophic cardiomyopathy (FHC) a¡ects up to 0.2% of the population and is the largest cause of sudden death in young adults (reviewed in ). It is characterised by hypertrophy of cardiac myocytes, disarray of muscle ¢bres, and an increase in connective tissue. It is caused by a mutation in one of a number of cytoskeletal proteins that make up the muscle sarcomere, including myosin, C-protein, troponin-T and I, K-tropomyosin and the ventricular light chains.
American journal of human genetics, 1990
We report that a gene responsible for familial hypertrophic cardiomyopathy (HC) is closely linked to the cardiac alpha and beta myosin heavy chain (MHC) genes on chromosome 14q11. We have recently shown that probe CRI-L436, derived from the anonymous DNA locus D14S26, detects a polymorphic restriction fragment that segregates with familial HC in affected members of a large Canadian family. Using chromosomal in situ hybridization, we have mapped CRI-L436 to chromosome 14 at q11-q12. Because the cardiac MHC genes also map to this chromosomal band, we have determined the genetic distances between the cardiac beta MHC gene, D14S26, and the familial HC locus. Data presented here show that these three loci are linked within 5 centimorgans on chromosome 14 at q11-q12. The possibility that defects in either the cardiac alpha or beta MHC genes are responsible for familial HC is discussed.
2010
Familial hypertrophic cardiomyopathy (HCM) is caused by mutations in 9 sarcomeric protein genes. The most commonly affected is -myosin heavy chain (MYH7), where missense mutations cluster in the head and neck regions and directly affect motor function. Comparable mutations have not been described in the light meromyosin (LMM) region of the myosin rod, nor would these be expected to directly affect motor function. We studied 82 probands with HCM in whom no mutations had been found in MYH7 exons encoding the head and neck regions of myosin nor in the other frequently implicated disease genes. Primers were designed to amplify exons 24 to 40 of MYH7. These amplimers were subjected to temperature modulated heteroduplex analysis by denaturing high-performance liquid chromatography. An Ala1379Thr missense mutation in exon 30 segregated with disease in three families and was not present in 200 normal chromosomes. The mutation occurred on two haplotypes, indicating that it was not a polymorp...