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| Genetische Analyse im M-Banden-Protein Myomesin bei Patienten mit Hypertropher Kardiomyopathie León Pérez, Verónica |
| Main title | Genetische Analyse im M-Banden-Protein Myomesin bei Patienten mit Hypertropher Kardiomyopathie |
| Title variations | Genetic Analyse of the M-band protein Myomesin in patients with hypertrophic cardiomyopathy |
| Author(s) | León Pérez, Verónica
Place of birth: Las Palmas de Gran Canaria, Spanien |
| 1. Referee | Prof. Dr. med. W. Haverkamp |
| Further Referee(s) | Prof. Dr. T. Kraft Prof. Dr. J.-C. Perriard |
| Keywords | myomesin; sarcomeric M-band; hypertrophic cardiomyopathy; mutation; genetic |
| Classification (DDC) | 610 Medical sciences; Medicine |
| Summary | Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac condition and the most important cause of sudden cardiac death (SCD) in the young population (Elliot and McKenna, 2004). The prevalence of hypertrophic cardiomyopathy is about one in 500 adults. (Maron et al., 1994 and Maron et al., 1995). Most adolescents and adults with hypertrophic cardiomyopathy have familial diesease with an autosomal pattern of inheritance. The clinical manifestations of HCM vary from a benign asymptomatic course to that of severe heart failure and SCD (Maron, 1997). HCM is diagnosed clinically by the presence of unexplained left ventricular hypertrophy (absence of hypertension, valvular disease, etc) and a small left ventricular cavity. The hypertrophy is predominantly asymmetric and in the majority of cases affects the interventricular septum. More than 400 mutations were identified in 13 different genes, most of them encode for sarcomeric proteins (Elliot and McKenna, 2004). Genetic data show that mutations in sarcomeric proteins account for only 60% of cases of the disease (Marian and Roberts, 2001; Seidman et al., 2001; Franz et al., 2001 and. Richard et al., 2003), suggesting the existence of more unknown disease genes. We propose in this study a novel diesease gene causing HCM: the myomesin gene (MYOM). The MYOM gene encodes for the protein Myomesin. Myomesin is a protein located on the M-band. The M-Band is a transversal structure in the center of sarcomere that is needed to maintain the regular packing and the precise alignment of thick filaments during sarcomere activation (Agarkova et al., 2003). It has been suggested that the M-band plays an important organizational role during myofibrillogenesis when the nascent thick filaments have to assemble and be aligned into a regular hexagonal lattice (Wang et al., 1998; Ehler et al., 1999; Yang et al., 2000). Methods Eight coding exons of MYOM were amplified using polymerase chain reaction (PCR): exons 7,8,9,22,23,24,25 and 26. Mutation screening was performed by single strand conformation polymorphism analysis (SSCP) under two different conditions with respect to gel composition and running temperature. The DNA banding patterns were visualized by silver staining. Samples with aberrant band patterns were subjected to automated sequencing of both strands. Screening for mutation Leu390Phe in MYOM within family S and controls was done by restricction enzym digestion with Dde I. Clinical evaluation was performed and blood samples were drawn from 410 unrelated patients with HCM and 307 control individuals. Results A total of 410 unrelated HCM patients were examined for genetic variants and mutations in MYOM. We identified a novel missense mutation in exon 7 of MYOM: Leu390Phe, in one unrelated individual out of 410 patients examined. Seven single nucleotide polymorphisms (SNPs) were identified in MYOM. Four of these SNPs were identified in exon 7; one in the coding region and three in the intronic region (c.1480 (Codon 382) and g.47309, g.47317, g.47355). Two SNPs were detected in the coding region of exon 9, one in the coding region (codon 464 (Arg464Arg)) and one in the intronic region (g.56910). A missense mutation was identified in the coding region of exon 9: c.1724 (Codon 464). The other SNP was identified in intron 22 (g121255). The identification of the mutation Leu390Phe in MYOM shows that this kind of mutation may cause HCM. The identification of several SNPs in the splice site of MYOM could be the starting point for further analysis to prove the influence of these SNPs on Myomesin and its function in the sarcomere. Furthermore it has been shown that a search for mutations is possible with related methods. This work is a contribution to the fundamental research of HCM. The increasing identificaion of HCM associated mutations enables better diagnosis and genetical consultation of the patients and hence an improvement of the treatment of HCM. |
| Documents |
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| FU Department | Department of Medicine - Charité - University Medicine Berlin |
| Year of publication | 2007 |
| Document type | Doctoral thesis |
| Media type/Format | Text |
| Language | German |
| Terms of use/Rights | Nutzungsbedingungen |
| Date of defense | 2007-12-14 |
| Created at | 2007-12-07 : 12:00:00 |
| Last changed | 2010-02-19 : 01:52:56 |
| Old Darwin URL | http://www.diss.fu-berlin.de/2007/846/ |
| Static URL | http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000002583 |
| NBN | urn:nbn:de:kobv:188-fudissthesis000000002583-0 |
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