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Type A Insulin Resistance Syndrome Revealing a Novel Lamin A Mutation

¹ Endocrinology and Reproductive Diseases Department, Assistance Publique-Hôpitaux de Paris, and INSERM U.693, Bicêtre Hospital, Le Kremlin-Bicêtre, Paris XI University, Paris, France
² INSERM U680, Saint-Antoine Faculty of Medicine, Pierre and Marie Curie University, Paris, France
³ Molecular Biology Department, Saint-Antoine Hospital, Paris, France
⁴ Radiology Department, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
⁵ Généthon CNRS UMR8115, Evry, France

Particular forms of polycystic ovary syndrome with severe hyperandrogenism, acanthosis nigricans, and marked insulin resistance, defining the type A insulin resistance syndrome, are due to insulin receptor gene mutations. However, the majority of affected individuals do not have such mutation, arguing for the genetic heterogeneity of this syndrome. The familial partial lipodystrophy of the Dunnigan type, one of the diseases due to mutations in the lamin A/C (LMNA) gene, is characterized by a lipodystrophic phenotype and shares some clinical and metabolic features with the type A syndrome. We describe here the case of a nonobese 24-year-old woman affected with type A syndrome without clinical lipodystrophy. We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family. The skin fibroblasts from the proband exhibited nuclear alterations similar to those described in other laminopathies, and showed several defects in the insulin transduction pathway. This study further extends the vast range of diseases linked to LMNA mutations and identifies another genetic cause for the type A insulin resistance syndrome.

Abbreviations: DEXA, dual-energy X-ray absorptiometry; ERK, extracellular regulated kinase; FPLD, familial partial lipodystrophy of the Dunnigan type; IRß, insulin receptor ß subunit; IRS-1, insulin receptor substrate-1; PCOS, polycystic ovary syndrome; PKB, protein kinase B

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