title: Multitissular involvement in a family with LMNA and EMD mutations: Role of digenic mechanism?
abstract: BACKGROUND
  Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes.
  
  
  METHODS
  Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin.
  
  
  RESULTS
  Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C-->T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts.
  
  
  CONCLUSIONS
  This highlights the crucial role of lamin A/C-emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery-Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 582, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Ben Yaou
authors.forename: A
authors.initials: A
authors.lastname: Toutain
authors.forename: T
authors.initials: T
authors.lastname: Arimura
authors.forename: L
authors.initials: L
authors.lastname: Demay
authors.forename: C
authors.initials: C
authors.lastname: Massart
authors.forename: C
authors.initials: C
authors.lastname: Peccate
authors.forename: A
authors.initials: A
authors.lastname: Muchir
authors.forename: S
authors.initials: S
authors.lastname: Llense
authors.forename: N
authors.initials: N
authors.lastname: Deburgrave
authors.forename: F
authors.initials: F
authors.lastname: Leturcq
authors.forename: K E
authors.initials: KE
authors.lastname: Litim
authors.forename: N
authors.initials: N
authors.lastname: Rahmoun-Chiali
authors.forename: P
authors.initials: P
authors.lastname: Richard
authors.forename: D
authors.initials: D
authors.lastname: Babuty
authors.forename: D
authors.initials: D
authors.lastname: Récan-Budiartha
authors.forename: G
authors.initials: G
authors.lastname: Bonne
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D004576:Electromyography; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006331:Heart Diseases / Q000235:genetics; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; C092710:emerin