caa a22 4500 445861967 CHVBK 20180317145446.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s00439-010-0909-1 doi (NATIONALLICENCE)springer-10.1007/s00439-010-0909-1 Modifier locus of the skeletal muscle involvement in Emery-Dreifuss muscular dystrophy [Elektronische Daten] [B. Granger, L. Gueneau, V. Drouin-Garraud, V. Pedergnana, F. Gagnon, R. Ben Yaou, S. Tezenas du Montcel, G. Bonne] Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki© software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211cM) with a Bayes factor of 28.7 (empirical p value=0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2years earlier for the homozygotes of the rare allele and 37years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy. Springer-Verlag, 2010 Granger B. Université Pierre et Marie Curie Paris 06, ER4, Modélisation en Recherche Clinique, 75013, Paris, France aut Gueneau L. Inserm, UMRS_974, 75013, Paris, France aut Drouin-Garraud V. Département de Génétique Médicale, Hôpital Charles Nicolle, 76000, Rouen, France aut Pedergnana V. Inserm, UMRS_974, 75013, Paris, France aut Gagnon F. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada aut Ben Yaou R. Inserm, UMRS_974, 75013, Paris, France aut Tezenas du Montcel S. Université Pierre et Marie Curie Paris 06, ER4, Modélisation en Recherche Clinique, 75013, Paris, France aut Bonne G. Inserm, UMRS_974, 75013, Paris, France aut Human Genetics Springer-Verlag 129/2(2011-02-01), 149-159 0340-6717 129:2<149 2011 129 439 https://doi.org/10.1007/s00439-010-0909-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00439-010-0909-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Granger B. Université Pierre et Marie Curie Paris 06, ER4, Modélisation en Recherche Clinique, 75013, Paris, France aut NATIONALLICENCE 700 1- Gueneau L. Inserm, UMRS_974, 75013, Paris, France aut NATIONALLICENCE 700 1- Drouin-Garraud V. Département de Génétique Médicale, Hôpital Charles Nicolle, 76000, Rouen, France aut NATIONALLICENCE 700 1- Pedergnana V. Inserm, UMRS_974, 75013, Paris, France aut NATIONALLICENCE 700 1- Gagnon F. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada aut NATIONALLICENCE 700 1- Ben Yaou R. Inserm, UMRS_974, 75013, Paris, France aut NATIONALLICENCE 700 1- Tezenas du Montcel S. Université Pierre et Marie Curie Paris 06, ER4, Modélisation en Recherche Clinique, 75013, Paris, France aut NATIONALLICENCE 700 1- Bonne G. Inserm, UMRS_974, 75013, Paris, France aut NATIONALLICENCE 773 0- Human Genetics Springer-Verlag 129/2(2011-02-01), 149-159 0340-6717 129:2<149 2011 129 439 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer