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Modifier locus of the skeletal muscle involvement in Emery–Dreifuss muscular dystrophy

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Abstract

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 (211 cM) 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 2 years earlier for the homozygotes of the rare allele and 37 years 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.

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Acknowledgments

We thank Michel Krawczyk from the Computer Center and Research Network of Jussieu (Paris, France) and Jean-Louis Gaunet from Pitié-Salpétrière Hospital (Paris, France) for their valuable methodological assistance; Véronique Ortega, Andoni Urtizberea, Denis Duboc, El-Hadi Hammouda and Henri-Marc Bécane for their precious help in the clinical evaluation of the EDM1 family. This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM); the Université Paris 06; the Centre National de la Recherche Scientifique (CNRS); the Association Française contre les Myopathies [#11057, #11034 and financial support for L.G.]; the European Union Sixth Framework Programme [Euro-laminopathies #018690] and F. G. holds a Canada Research Chair.

Conflict of interest

There is no direct or indirect conflict of interest for any of the authors for the data presented in the manuscript in whole or in part.

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Authors and Affiliations

  1. Université Pierre et Marie Curie Paris 06, ER4, Modélisation en Recherche Clinique, 75013, Paris, France

    B. Granger & S. Tezenas du Montcel

  2. Unité de Biostatistiques et Informatique Médicale, Centre Hospitalo-universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013, Paris, France

    B. Granger & S. Tezenas du Montcel

  3. Inserm, UMRS_974, 75013, Paris, France

    L. Gueneau, V. Pedergnana, R. Ben Yaou & G. Bonne

  4. Université Pierre et Marie Curie-Paris 6, UM 76, CNRS, UMR7215, Institut de Myologie, IFR14, 75013, Paris, France

    L. Gueneau, V. Pedergnana, R. Ben Yaou & G. Bonne

  5. Département de Génétique Médicale, Hôpital Charles Nicolle, 76000, Rouen, France

    V. Drouin-Garraud

  6. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

    F. Gagnon

  7. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, 75013, Paris, France

    G. Bonne

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  1. B. Granger
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  2. L. Gueneau
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Correspondence to B. Granger.

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The authors wish it to be known that, in their opinion, the B. Granger, L. Gueneau authors should be regarded as joint first authors and the S. Tezenas du Montcel, G. Bonne authors should be regarded as joint last authors.

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439_2010_909_MOESM1_ESM.jpeg

Schematic presentation of candidate gene regions that were sequenced. Arrows indicated positions of the primers used for sequencing Supplementary material 2 (DOCX 29 kb)

Supplementary material 2 (DOCX 29 kb)

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Granger, B., Gueneau, L., Drouin-Garraud, V. et al. Modifier locus of the skeletal muscle involvement in Emery–Dreifuss muscular dystrophy. Hum Genet 129, 149–159 (2011). https://doi.org/10.1007/s00439-010-0909-1

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