title: Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome.
abstract: BACKGROUND
  Laminopathies, due to mutations in LMNA, encoding A type-lamins, can lead to premature ageing and/or lipodystrophic syndromes, showing that these diseases could have close physiopathological relationships. We show here that lipodystrophy and extreme insulin resistance can also reveal the adult progeria Werner syndrome linked to mutations in WRN, encoding a RecQ DNA helicase.
  
  
  METHODS
  We analysed the clinical and biological features of two women, aged 32 and 36, referred for partial lipodystrophic syndrome which led to the molecular diagnosis of Werner syndrome. Cultured skin fibroblasts from one patient were studied.
  
  
  RESULTS
  Two normal-weighted women presented with a partial lipodystrophic syndrome with hypertriglyceridemia and liver steatosis. One of them had also diabetes. Both patients showed a peculiar, striking lipodystrophic phenotype with subcutaneous lipoatrophy of the four limbs contrasting with truncal and abdominal fat accumulation. Their oral glucose tolerance tests showed extremely high levels of insulinemia, revealing major insulin resistance. Low serum levels of sex-hormone binding globulin and adiponectin suggested a post-receptor insulin signalling defect. Other clinical features included bilateral cataracts, greying hair and distal skin atrophy. We observed biallelic WRN null mutations in both women (p.Q748X homozygous, and compound heterozygous p.Q1257X/p.M1329fs). Their fertility was decreased, with preserved menstrual cycles and normal follicle-stimulating hormone levels ruling out premature ovarian failure. However undetectable anti-müllerian hormone and inhibin B indicated diminished follicular ovarian reserve. Insulin-resistance linked ovarian hyperandrogenism could also contribute to decreased fertility, and the two patients became pregnant after initiation of insulin-sensitizers (metformin). Both pregnancies were complicated by severe cervical incompetence, leading to the preterm birth of a healthy newborn in one case, but to a second trimester-abortion in the other. WRN-mutated fibroblasts showed oxidative stress, increased lamin B1 expression, nuclear dysmorphies and premature senescence.
  
  
  CONCLUSIONS
  We show here for the first time that partial lipodystrophy with severe insulin resistance can reveal WRN-linked premature aging syndrome. Increased expression of lamin B1 with altered lamina architecture observed in WRN-mutated fibroblasts could contribute to premature cellular senescence. Primary alterations in DNA replication and/or repair should be considered as possible causes of lipodystrophic syndromes.
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, F-75012, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Donadille
authors.forename: Pascal
authors.initials: P
authors.lastname: D'Anella
authors.forename: Martine
authors.initials: M
authors.lastname: Auclair
authors.forename: Nancy
authors.initials: N
authors.lastname: Uhrhammer
authors.forename: Marc
authors.initials: M
authors.lastname: Sorel
authors.forename: Romulus
authors.initials: R
authors.lastname: Grigorescu
authors.forename: Sophie
authors.initials: S
authors.lastname: Ouzounian
authors.forename: Gilles
authors.initials: G
authors.lastname: Cambonie
authors.forename: Pierre
authors.initials: P
authors.lastname: Boulot
authors.forename: Pascal
authors.initials: P
authors.lastname: Laforêt
authors.forename: Bruno
authors.initials: B
authors.lastname: Carbonne
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
authors.forename: Yves-Jean
authors.initials: YJ
authors.lastname: Bignon
authors.forename: Corinne
authors.initials: C
authors.lastname: Vigouroux
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007333:Insulin Resistance / Q000235:genetics*; D008060:Lipodystrophy / Q000150:complications* / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D011247:Pregnancy; D053484:RecQ Helicases / Q000235:genetics*; D012867:Skin / Q000166:cytology; D014898:Werner Syndrome / Q000150:complications* / Q000175:diagnosis / Q000235:genetics*; D000071657:Werner Syndrome Helicase
chemical_list: D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase