Partial lipodystrophy with severe insulin resistance and adult progeria Werner syndrome

Orphanet Journal of Rare Diseases

Corinne Vigouroux³  Yves-Jean Bignon^1,11  Sophie Christin-Maitre⁵  Bruno Carbonne⁷  Pascal Laforêt⁹  Pierre Boulot⁴  Gilles Cambonie¹  Sophie Ouzounian²  Romulus Grigorescu⁸  Marc Sorel^1,10  Nancy Uhrhammer^1,11  Martine Auclair³  Pascal D’Anella⁶  Bruno Donadille² 

[1] Hôpital A. de Villeneuve, Pédiatrie néonatale, F-34295, Montpellier, France;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Endocrinologie, Diabétologie et Endocrinologie de la Reproduction, F-75012, Paris, France;ICAN Institute of Cardiometabolism and Nutrition, Groupe Hospitalier Universitaire La Pitié Salpêtrière, Paris, France;Hôpital A. de Villeneuve, Gynéco-Obstétrique, F-34295, Montpellier, France;INSERM U933, F-75012, Paris, France;Hôpital Henri Duffaut, Endocrinologie-Maladies Métaboliques, F-84902, Avignon, France;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Armand-Trousseau, Unité d'Obstétrique-Maternité, F-75012, Paris,France;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Armand-Trousseau, Génétique et Embryologie, F- 75012, Paris, France;Centre de Référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, AP-HP, F-75013, Paris, France;Centre Hospitalier de Nemours, Centre d’Evaluation et de Traitement de la Douleur, and EA 4391, Faculté de médecine, Université Paris-Est Créteil, F-77796, Nemours, France;Centre Jean Perrin, Laboratoire de diagnostic génétique et moléculaire, F-63000, Clermont-Ferrand, France

关键词: Lamin B1;    Prelamin A;    Cervical insufficiency;    Decreased ovarian reserve;    Pregnancy;    Progeria;    Premature aging;    WRN gene;    Insulin resistance;    Lipodystrophy;   

Others  :  863649
DOI  :  10.1186/1750-1172-8-106

 received in 2013-03-27, accepted in 2013-07-03,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Donadille et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

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