A Newly Created Splice Donor Site in Exon 25 of the MyBP-C Gene Is Responsible for Inherited Hypertrophic Cardiomyopathy With Incomplete Disease Penetrance
| Autor: | Christine Fischer, Sebastian Reith, Sonja Bailey, Julia Ochs, Heinz Klues, William J. McKenna, Mathias Gautel, Brigitte Jeschke, Kerstin Uhl, Johannes A. Moolman, Hans-Peter Vosberg |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Heterozygote Genotype Genetic Linkage Immunoblotting Cardiomyopathy Penetrance Locus (genetics) Biology Electrocardiography Exon Genetic linkage Physiology (medical) medicine Humans Missense mutation Age of Onset Aged Genetics Chromosomes Human Pair 11 Hypertrophic cardiomyopathy Exons Myocardial Disorder Cardiomyopathy Hypertrophic Middle Aged medicine.disease Phenotype Echocardiography Mutation Female Carrier Proteins Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation. 101:1396-1402 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background —Hypertrophic cardiomyopathy is a myocardial disorder resulting from inherited sarcomeric dysfunction. We report a mutation in the myosin-binding protein-C (MyBP-C) gene, its clinical consequences in a large family, and myocardial tissue findings that may provide insight into the mechanism of disease. Methods and Results —History and clinical status (examination, ECG, and echocardiography) were assessed in 49 members of a multigeneration family. Linkage analysis implicated the MyBP-C gene on chromosome 11. Myocardial mRNA, genomic MyBP-C DNA, and the myocardial proteins of patients and healthy relatives were analyzed. A single guanine nucleotide insertion in exon 25 of the MyBP-C gene resulted in the loss of 40 bases in abnormally processed mRNA. A 30-kDa truncation at the C-terminus of the protein was predicted, but a polypeptide of the expected size (≈95 kDa) was not detected by immunoblot testing. The disease phenotype in this family was characterized in detail: only 10 of 27 gene carriers fulfilled diagnostic criteria. Five carriers showed borderline hypertrophic cardiomyopathy, and 12 carriers were asymptomatic, with normal ECG and echocardiograms. The age of onset in symptomatic patients was late (29 to 68 years). In 2 patients, outflow obstruction required surgery. Two family members experienced premature sudden cardiac death, but survival at 50 years was 95%. Conclusions —Penetrance of this mutation was incomplete and age-dependent. The large number of asymptomatic carriers and the good prognosis support the interpretation of benign disease. |
| Databáze: | OpenAIRE |
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