Identification of the Syrian hamster cardiomyopathy gene (original) (raw)
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Proceedings of the National Academy of Sciences, 1997
Cardiomyopathy (CM) is a primary degenerative disease of myocardium and is traditionally categorized into hypertrophic and dilated CMs (HCM and DCM) according to its gross appearance. Cardiomyopathic hamster (CM hamster), a representative model of human hereditary CM, has HCM and DCM inbred sublines, both of which descend from the same ancestor. Herein we show that both HCM and DCM hamsters share a common defect in a gene for δ-sarcoglycan (δ-SG), the functional role of which is yet to be characterized. A breakpoint causing genomic deletion was found to be located at 6.1 kb 5′ upstream of the second exon of δ-SG gene, and its 5′ upstream region of more than 27.4 kb, including the authentic first exon of δ-SG gene, was deleted. This deletion included the major transcription initiation site, resulting in a deficiency of δ-SG transcripts with the consequent loss of δ-SG protein in all the CM hamsters, despite the fact that the protein coding region of δ-SG starting from the second exon...
FEBS Letters, 1999
The N N-sarcoglycan (SG) gene is deleted in hamsters with hereditary cardiomyopathies. Immunological analyses of heart before, but not after, the progression of cardiomyopathy (CM) revealed that the BIO 14.6 strain, a model of hypertrophic CM, heterogeneously preserved K K-and Q Q-SG with loss of L L-and N N-SG. In contrast, the TO-2 strain, a model of dilated CM, did not show either SG. Furthermore, in vivo transfer of the full length N N-SG gene to TO-2 hearts expressed all four SGs. Thus, this age-and strain-dependent features suggest a more feasible setting for TO-2 than BIO 14.6 to verify both CM progression and the efficacy of gene therapy.
Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by β sarcoglycan mutations
Journal of Medical Genetics, 2000
Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaVected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of and sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. DiVering expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in and sarcoglycans, we show for the first time that the condition can also be caused by mutations in the sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.
Journal of Medical Genetics, 2000
Two young males with limb-girdle muscular dystrophy (LGMD) resulting from sarcoglycan deficiency died at 27 (patient 1) and 18 years (patient 2) of severe cardiomyopathy. Genetic analysis showed that they were compound heterozygotes for mutations in the sarcoglycan gene. One of these mutations, an 8 bp duplication in exon 3, was common to both patients. The second mutation in patient 2 was a 4 bp deletion at the splice donor site of intron 2, not reported previously. Patient 2 had more severe heart and skeletal muscle defects with faster deterioration; no sarcoglycans were detected in his skeletal muscle. The second mutation in patient 1, inferred because the unaVected father carries the 8 bp duplication, was not found. In patient 1, both heart and skeletal muscle were analysed and showed reduction of all sarcoglycans in both tissues and incorrect localisation of and sarcoglycans in heart. Therefore mutations in one sarcoglycan gene can disrupt the entire sarcoglycan complex in both skeletal and cardiac muscle. DiVering expression patterns of sarcoglycan components in heart and skeletal muscle could be the result of alternatively spliced transcripts in these tissues. By sequencing an alternative transcript, highly expressed in the heart and skeletal muscle of patient 1, we found an 87 bp cryptic exon not previously reported. Although cardiomyopathy can result from mutations in and sarcoglycans, we show for the first time that the condition can also be caused by mutations in the sarcoglycan gene. This report therefore expands the phenotype of sarcoglycanopathies and suggests that cardiac function in LGMD patients with defective sarcoglycan expression should be monitored.
A novel mutation, Arg71Thr, in the ?-sarcoglycan gene is associated with dilated cardiomyopathy
Journal of Molecular Medicine, 2003
Approximately 20-35% of cases of idiopathic dilated cardiomyopathy are familial. DCM-associated mutations have been reported in 13 genes including the desmin, d-sarcoglycan, and metavinculin genes. This study screened for variants in these genes in Finnish patients with DCM. All coding regions of the desmin and d-sarcoglycan genes and the metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients from eastern Finland by PCR-SSCP. We detected a novel mutation, Arg71Thr, in the d-sarcoglycan gene in two members of a small DCM family. One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function. Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a late onset of the disease. Disease-associated mutations were not found in the desmin gene or the metavinculin-specific exon of the vinculin gene. We conclude that the desmin and dsarcoglycan genes are not predominant disease-causing genes in patients with DCM in eastern Finland.
Circulation. Heart failure, 2011
The BIO14.6 hamster provides a useful model of hereditary cardiomyopathies and muscular dystrophy. Previous δ-sarcoglycan (δSG) gene therapy (GT) studies were limited to neonatal and young adult animals and prevented the development of cardiac and skeletal muscle dysfunction. GT of a pseudophosphorylated mutant of phospholamban (S16EPLN) moderately alleviated the progression of cardiomyopathy. We treated 4-month-old BIO14.6 hamsters with established cardiac and skeletal muscle diseases intravenously with a serotype-9 adeno-associated viral vector carrying δSG alone or in combination with S16EPLN. Before treatment at age 14 weeks, the left ventricular fractional shortening by echocardiography was 31.3% versus 45.8% in normal hamsters. In a randomized trial, GT halted progression of left ventricular dilation and left ventricular dysfunction. Also, respiratory function improved. Addition of S16EPLN had no significant additional effects. δSG-GT prevented severe degeneration of the trans...
Sarcomeric proteins and inherited cardiomyopathies
Cardiovascular Research, 2007
Over the last two decades, a large number of mutations have been identified in sarcomeric proteins as a cause of hypertrophic, dilated or restrictive cardiomyopathy. Functional analyses of mutant proteins in vitro have revealed several important functional changes in sarcomeric proteins that might be primarily involved in the pathogenesis of each cardiomyopathy. Creation of transgenic or knock-in animals expressing mutant proteins in their hearts confirmed that these mutations in genes for sarcomeric proteins induced distinct types of cardiomyopathies and provided useful animal models to explore the molecular pathogenic mechanisms and potential therapeutics of cardiomyopathy in vivo. In this review, I discuss the functional consequences of mutations in different sarcomeric proteins found in hypertrophic, dilated, and restrictive cardiomyopathies in conjunction with their effects on cardiac structure and function in vivo and their possible molecular and cellular mechanisms, which underlie the pathogenesis of these inherited cardiomyopathies.
Journal of the American College of Cardiology, 2020
Background: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are life threatening diseases described by abnormal structure and function of the heart muscle in the absence of any secondary causes. Various genetic mutations were found to cause to HCM and DCM, mostly following autosomal dominant inheritance. However, the full spectrum of the causative mutations remains to be discovered especially in understudied populations. Methods: Here, we established the DOHA Registry and Biobank for cardiomyopathies, at the Heart Hospital in Qatar, followed by targeted sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. Results: Pathogenic variants were identified in 45% (23 cases) and 35% (19 cases) of HCM and DCM cases, while 7% (4 cases), 15% (8 cases) of HCM and DCM cases did not have any pathogenic or putative pathogenic variants, respectively, and will require further genetic investigations. Moreover, a total of 28 novel sarcomere gene variants were identified in HCM and DCM, 20 of those were in TTN gene. Finally, the study identified possible Arabic founder mutations including a variants in FKTN which could cause DCM in homozygosity and HCM, in heterozygosity. Conclusion: Further functional validation is required to assess the pathogenicity of the identified variants.
Sarcomeric hypertrophic cardiomyopathy: Genetic profile in a Portuguese population
Revista Portuguesa de Cardiologia, 2012
Background: Sarcomeric hypertrophic cardiomyopathy has heterogeneous phenotypic expressions, of which sudden cardiac death is the most feared. A genetic diagnosis is essential to identify subjects at risk in each family. The spectrum of disease-causing mutations in the Portuguese population is unknown. Methods: Seventy-seven unrelated probands with hypertrophic cardiomyopathy were systematically screened for mutations by PCR and sequencing of five sarcomeric genes: MYBPC3, MYH7, TNNT2, TNNI3 and MYL2. Familial cosegregation analysis was performed in most patients. Results: Thirty-four different mutations were identified in 41 (53%) index patients, 71% with familial hypertrophic cardiomyopathy. The most frequently involved gene was MYBPC3 (66%) with 22 different mutations (8 novel) in 27 patients, followed by MYH7 (22%), TNNT2 (12%) and TNNI3 (2.6%). In three patients (7%), two mutations were found in MYBPC3 and/or MYH7. Additionally, 276 relatives were screened, leading to the identification of a mean of three other affected relatives for each pedigree with the familial form of the disease. Conclusions: Disease-associated mutations were identified mostly in familial hypertrophic cardiomyopathy, corroborating the idea that rarely studied genes may be implicated in sporadic forms. Private mutations are the rule, MYBPC3 being the most commonly involved gene. Mutations in MYBPC3 and MYH7 accounted for most cases of sarcomere-related disease. Multiple mutations in these genes may occur, which highlights the importance of screening both. The detection of novel mutations strongly suggests that all coding regions should be systematically screened. Genotyping in hypertrophic cardiomyopathy enables a more precise diagnosis of the disease, with implications for risk stratification and genetic counseling.