title: A novel phenotypic expression associated with a new mutation in LMNA gene, characterized by partial lipodystrophy, insulin resistance, aortic stenosis and hypertrophic cardiomyopathy.
abstract: BACKGROUND
  Lipodystrophies are a heterogeneous group of diseases characterized by abnormal fat distribution. Familial partial lipodystrophy 2 (FPLD2) is due to mutations in the LMNA gene. Previous studies have suggested that LMNA mutations 5' to the nuclear localization signal (NLS) are more likely to underlie laminopathies with cardiac or skeletal muscle involvement, while mutations 3' to the NLS are more likely to underlie lipodystrophy and progeroid syndromes.
  
  
  OBJECTIVE
  To study the clinical and molecular features of a subject with FPLD.
  
  
  METHODS
  We carried out mutational analysis of LMNA gene in a woman with FPLD phenotype and in her relatives. Insulin resistance was evaluated by minimal model. Body composition was evaluated by dual-energy X-ray absorptiometry (DEXA). Echocardiography was done in affected subjects. 3T3-L1 preadipocytes were transfected with wild-type or mutant prelamin A constructs. In transfected cells, lamin A was detected using a Cy3-conjugated monoclonal anti-FLAG antibody.
  
  
  RESULTS
  The patient showed atypical fat distribution, insulin resistance, severe aortic stenosis and hypertrophic cardiomyopathy. She has an affected 11-year-old son, not yet lipodystrophic but with an incipient aortic disease. LMNA sequencing showed that mother and son were both heterozygous for a novel c.1772G > T missense mutation in exon 11, which causes the substitution of the cysteine at residue 591 by a phenylalanine (C591F). In mouse preadipocytes transfected with the mutant human LMNA gene, the mutant lamin A isoform was mislocated in the nucleus.
  
  
  CONCLUSIONS
  This patient shows a novel clinical form of FPLD2, due to a mutation affecting lamin A only, with cardiac involvement.
authors.affiliation: Thyroid and Metabolic Diseases Unit (UETeM), Department of Medicine, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. medarvi@usc.es
authors.forename: David
authors.initials: D
authors.lastname: Araújo-Vilar
authors.forename: Joaquin
authors.initials: J
authors.lastname: Lado-Abeal
authors.forename: Fernando
authors.initials: F
authors.lastname: Palos-Paz
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Bandín
authors.forename: Diego
authors.initials: D
authors.lastname: Bellido
authors.forename: Lourdes
authors.initials: L
authors.lastname: Domínguez-Gerpe
authors.forename: Carlos
authors.initials: C
authors.lastname: Calvo
authors.forename: Oscar
authors.initials: O
authors.lastname: Pérez
authors.forename: Alia
authors.initials: A
authors.lastname: Ramazanova
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.forename: Berta
authors.initials: B
authors.lastname: Victoria
authors.forename: Ana Teresa
authors.initials: AT
authors.lastname: Costa-Freitas
mesh_terms: D041721:3T3-L1 Cells; D000328:Adult; D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000235:genetics*; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D034904:Lamin Type A / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000150:complications / Q000235:genetics*; D051379:Mice; D009154:Mutation / Q000502:physiology; D010375:Pedigree; D010641:Phenotype
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A