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|Suche nach Varianten im Myomesin-Gen bei Hypertropher Kardiomyopathie|
|Main title||Suche nach Varianten im Myomesin-Gen bei Hypertropher Kardiomyopathie|
|Subtitle||eine genetische Analyse|
|Title variations||Variants in the myomesin gene in hypertrophic cardiomyopathy|
|Subtitle for translated title||a genetic analysis|
Place of birth: Duisburg, Deutschland
|1. Referee||Prof. Dr. med. K. J. Osterziel|
|Further Referee(s)||Prof. Dr. D. Fürst
Prof. Dr. med. H. Tillmanns
|Keywords||myomesin cardiomyopathy hypertrophic dilatative m-band|
|Classification (DDC)||610 Medical sciences; Medicine|
|Summary||Hypertrophic Cardiomyopathy (HCM) is a widely spread genetically caused disease of the cardiac muscle with a prevalence of 1:500. It is characterised by myocardial hypertrophy and a high risk of sudden cardiac death. So far twelve genes have been identified which are associated with HCM. Most of these genes encode for sarcomeric proteins. The protein Myomesin which is localized in the sarcomeric m-band has been hardly analyzed up to now. Therefore the aim of this work was to look for HCM-causing mutations within the myomesin gene.
Methods: 351 not related patients with idiopathic HCM were examinated by physical examination, electrocardiography and echocardiography. The DNA of these patients was extracted from blood lymphocytes. The Exons 27 up to 36 of the myomesin gene were amplified by polymerase chain reaction and screened for mutations by SSCP (single strand conformation polymorphism). Samples with a striking band pattern were analyzed by sequencing.
Results: The exons 28 and 34 showed a polymorphic band pattern after SSCP analysis. Sequencing of Exon 34 showed three mutations, namely in the intron before, in the intron after and a silent mutation within the exon. Sequencing of exon 28 produced several intronic mutations. None of these SNPs cause an amino acid exchange. Seemingly they dont influence the splicing process. SSCP of the exons 31/32 showed a conspicuous band pattern. After sequencing a missense mutation in exon 32 was found in the sample of a Polish patient. The mutation was confirmed by enzymatic digestion. The mutation results in an amino acid exchange of valine to isoleucine at position 1394. The amino acid affected by this mutation is localized in a well conserved position within domain 12 of the protein. Its hydrophobic residue points at the core of a beta-sheet. An exchange of valine by isoleucine at this position might lead to a functional alteration of the protein. The mutation was inherited in the patients family. Six of eleven examined members of the family are mutation carriers. Three of the carriers have got HCM. The other three carriers were 23 and 26 years old at the date of the examination. The mutation seems to be associated with a manifestation of HCM during middle age. The interventricular septum of the diseased showed a thickness of 15 to 18mm.
Conclusion: A missense mutation was found within the myomesin gene. It showed a cosegregation with a phenotypical HCM manifesting during middle age. In order to make a definite statement concernig its malignance further patients carrying this mutation would have to be found.
|FU Department||Department of Medicine - Charité - University Medicine Berlin|
|Year of publication||2006|
|Document type||Doctoral thesis|
|Date of defense||2006-06-02|
|Created at||2006-07-18 : 12:00:00|
|Last changed||2010-02-19 : 11:38:09|
|Old Darwin URL||http://www.diss.fu-berlin.de/2006/372/|