title: A LMNA splicing mutation in two sisters with severe Dunnigan-type familial partial lipodystrophy type 2.
abstract: BACKGROUND
  To date, all cases of familial partial lipodystrophy type 2 (FPLD2; Mendelian Inheritance in Man 151660) result from missense mutations in LMNA, which encodes nuclear lamin A/C (Mendelian Inheritance in Man 150330).
  
  
  OBJECTIVE
  The objective of the study was to carry out mutational analysis of LMNA in two sisters with a particularly severe FPLD2 phenotype.
  
  
  METHODS
  This was a descriptive case report with molecular studies.
  
  
  METHODS
  The study was conducted at a referral center.
  
  
  METHODS
  We report two sisters of South Asian origin. The first presented with acanthosis nigricans at age 5 yr, diabetes with insulin resistance, hypertension and hypertriglyceridemia at age 13 yr, and partial lipodystrophy starting at puberty. Her sister and their mother had a similar metabolic profile and physical features, and their mother died of vascular disease at age 32 yr.
  
  
  METHODS
  There were no interventions.
  
  
  RESULTS
  LMNA sequencing showed that the sisters were each heterozygous for a novel G>C mutation at the intron 8 consensus splice donor site, which was absent from the genomes of 300 healthy individuals. The retention of intron 8 in mRNA predicted a prematurely truncated lamin A isoform (516 instead of 664 amino acids) with 20 nonsense 3'-terminal residues. The mutant lamin A isoform failed to interact normally with emerin and failed to localize to the nuclear envelope.
  
  
  CONCLUSIONS
  This is the first LMNA splicing mutation to be associated with FPLD2, and it causes a severe clinical and metabolic phenotype.
authors.affiliation: Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Chantal F
authors.initials: CF
authors.lastname: Morel
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Thomas
authors.forename: Henian
authors.initials: H
authors.lastname: Cao
authors.forename: Caroline H
authors.initials: CH
authors.lastname: O'Neil
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
mesh_terms: D000052:Acanthosis Nigricans / Q000150:complications / Q000235:genetics; D000328:Adult; D001208:Asia / Q000208:ethnology; D015153:Blotting, Western; D002170:Canada; D004252:DNA Mutational Analysis; D003923:Diabetes Mellitus, Lipoatrophic / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D015228:Hypertriglyceridemia / Q000150:complications / Q000235:genetics; D007333:Insulin Resistance; D007438:Introns / Q000235:genetics; D034904:Lamin Type A / Q000235:genetics*; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D013946:Thymopoietins / Q000032:analysis / Q000378:metabolism; D014162:Transfection
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D013946:Thymopoietins; C092710:emerin