Expression of lamin A mutated in the carboxyl-terminal tail generates an aberrant nuclear phenotype similar to that observed in cells from patients with Dunnigan-type partial lipodystrophy and Emery-Dreifuss muscular dystrophy.
Autosomal dominantly inherited missense mutations in lamins A and C cause familial partial lipodystrophy of the Dunnigan-type (FPLD), and myopathies including Emery-Dreifuss muscular dystrophy (EDMD). While mutations responsible for FPLD are restricted to the carboxyl-terminal tails, those responsible for EDMD are spread throughout the molecules. We observed here the same structural abnormalities in the nuclear envelope and chromatin of fibroblasts from patients with FPLD and EDMD, harboring missense mutations at codons 482 and 453, respectively. Similar nuclear alterations were generated in fibroblasts, myoblasts, and preadipocytes mouse cell lines overexpressing lamin A harboring either of these two mutations. A large variation in sensitivity to lamin A overexpression was observed among the three cell lines, which was correlated with their variable endogenous content in A-type lamins and emerin. The occurrence of nuclear abnormalities was reduced when lamin B1 was coexpressed with mutant lamin A, emphasizing the functional interaction of the two types of lamins. Transfected cells therefore develop similar phenotypes when expressing lamins mutated in the carboxyl-terminal tail at sites responsible for FPLD or EDMD.
Favreau
Catherine
C
Département de Biologie Cellulaire, Institut Jacques Monod, CNRS, Universités Paris 6 & 7, 75251, Paris Cedex 05, France.
Dubosclard
Emmanuelle
E
Ostlund
Cecilia
C
Vigouroux
Corinne
C
Capeau
Jacqueline
J
Wehnert
Manfred
M
Higuet
Dominique
D
Worman
Howard J
HJ
Courvalin
Jean-Claude
JC
Buendia
Brigitte
B
D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics*; D032446:Myoblasts / Q000378:metabolism / Q000473:pathology; D009685:Nuclear Envelope / Q000378:metabolism / Q000473:pathology; D022022:Nuclear Pore / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000502:physiology
D002843:Chromatin; D034904:Lamin Type A; D034921:Lamin Type B