Résumé :
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The gene defects underlying the autosomal dominant late onset distal myopathy tibial muscular dystrophy (TMD, OMIM #600334 Udd myopathy) are in the titin (TTN) gene. TTN codes for the sarcomeric giant protein titin spanning one half sarcomere in striated muscle. We reported the first TMD causing TTN mutation, the Finnish complex founder mutation, FINmaj, g.293269_293279delAAGTAACATGGinsTGAAAGAAAAA in 2002 in the last exon, Mex6, of the gene. So far FINmaj is the only mutation found in Finland, where the currently known patient number indicates a prevalence of > 10 in 100,000 but the true prevalence of the disease is estimated to be higher. Currently seven different TTN mutations in the two last exons Mex5 and 6 with a dominant negative effect causing TMD titinopathy in European populations have been published, and a few more are known but still unpublished. There are several European families with known C-terminal TTN mutations, in which affected patients show a more complex or varying phenotype. This may indicate the presence of possible additional causative genetic changes in the TTN alleles, changes in other genes, or differences in the general genetic constitution. Alternatively this is caused by other unknown environmental factor affecting the phenotype. We have indication of an unbalance in the expression level of the two TTN alleles in one case from Finland heterozygous for the FINmaj mutation, and possibly in one Spanish case heterozygous for the previously reported Mex6 g.293378delA mutation. In the Finnish case the detected FINmaj allele seems to be clearly over expressed on the cDNA level. In addition we have found previously unreported basepair changes in the introns preceding exons Mex 5 and 6 in the case from Finland and one from Sweden. In the Swedish case we have not been able to find any causative mutation in the C-terminal exons of TTN so far. Results indicating whether or not these intronal changes are affecting splicing or expression levels of TTN are still pending. Analysis is ongoing to determine on which allele the observed basepair changes are located and if they could possibly affect TTN expression. Western blots were run on the Finnish and Spanish sample, showing clear reduction of the C-terminal TTN protein fragments. Analysis on genomic and expression level is continuing with the aim of clarifying reasons for the varying phenotypes.
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