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Prevalence of Mutations in AGPAT2 Among Human Lipodystrophies

¹ INSERM U.402, Saint-Antoine Faculty of Medicine, University of Pierre and Marie Curie, Paris, France
² National Center of Genotyping, Evry, France
³ Center of Human Genetics, Institute of Pathology and Genetics, Loverval, Belgium
⁴ Department of Pediatric Diabetology, Necker Hospital, Paris, France
⁵ Sylvius Laboratory, University of Leiden Medical Center, Leiden, the Netherlands
⁶ Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
⁷ Department of Pediatrics, da Crianca Institute, University of Sao Paulo, Sao Paulo, Brazil
⁸ Department of Pediatric Endocrinology, Robert Debré Hospital, Paris, France
⁹ Department of Clinical Genetics, Charles University, Prague, Czech Republic
¹⁰ Department of Child Health, King’s College Hospital, London, U.K
¹¹ Department of Medical Genetics, Pellegrin-Enfants Hospital, Bordeaux, France
¹² Joslin Diabetes Center, Harvard University, Boston, Massachusetts

Berardinelli-Seip congenital lipodystrophy (BSCL) is a heterogeneous genetic disease characterized by near absence of adipose tissue and severe insulin resistance. We have previously identified mutations in the seipin gene in a subset of our patients’ cohort. Recently, disease-causing mutations in AGPAT2 have been reported in BSCL patients. In this study, we have performed mutation screening in AGPAT2 and the related AGPAT1 in patients with BSCL or other forms of lipodystrophy who have no detectable mutation in the seipin gene. We found 38 BSCL patients from 30 families with mutations in AGPAT2. Three of the known mutations were frequently found in our families. Of the eight new alterations, six are null mutations and two are missense mutations (Glu172Lys and Ala238Gly). All the patients harboring AGPAT2 mutations presented with typical features of BSCL. We did not find mutations in patients with other forms of lipodystrophies, including the syndromes of Lawrence, Dunnigan, and Barraquer-Simons, or with type A insulin resistance. In conclusion, mutations in the seipin gene and AGPAT2 are confined to the BSCL phenotype. Because we found mutations in 92 of the 94 BSCL patients studied, the seipin gene and AGPAT2 are the two major genes involved in the etiology of BSCL.

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