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Identification of the gene altered in Berardinelli–Seip congenital lipodystrophy on chromosome 11q13

Nature Genetics volume 28, pages 365–370 (2001)Cite this article

Abstract

Congenital generalized lipodystrophy, or Berardinelli–Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance1,2,3,4. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity5. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), γ3-linked gene6 (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

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Figure 1: BSCL patients and their families from two geographical clusters, Lebanon and Norway, used for genome-wide linkage analysis and homozygosity mapping.
Figure 2: Haplotype analysis in families of various ethnic origins in which the disease is inferred to cosegregate with locus 11q13.
Figure 3: Seipin characterization.
Figure 4: Molecular alterations in BSCL2.
Figure 5: Expression of BSCL2.

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Acknowledgements

We thank the patients and their families for their participation; all the contributors for the families' collections, including the Medical Genetic Unit in Beyrouth; A. Lemainque, A. Faure, V. La Villa, S. Pavek, F. Cavallin and L. Bodson for genotyping; R. Schaaning Jörgensen and A. Gjesti for their technical assistance; P. Balladur, M. Chawatt and their collaborators for adipose tissues; B. Surin for quantification of RNA expression; D. Recan and her colleagues for immortalization of lymphocytes; Y. Chrétien, N. Chignard, L. Grivot, B. Jacquin and C. Lestringuez for computer assistance; and B. Guilmart for critical reading of the manuscript. This work was supported by grants from Aide aux Jeunes Diabétiques, Anders Jahres Fond, Assistance Public-Hôpitaux de Paris, the European Commission (contract BMH4-CT 97-4841), INSERM, Medinnova and the Ministère de la Recherche. This article is dedicated to the memory of Martin Seip (1921–2001).

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Authors and Affiliations

  1. INSERM U.402, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, 27 rue Chaligny, Paris, 75012, France

    Jocelyne Magré, Muriel Meier & Jacqueline Capeau

  2. Centre National de Génotypage, Evry, Paris, France

    Marc Delépine, Eric Sobel, Jeanette Papp & Mark Lathrop

  3. Service de Pédiatrie, Hôtel-Dieu de France, Beyrouth, Lebanon

    Eliane Khallouf

  4. Institute of Forensic Medicine and Departments of Dermatology, Internal Medicine and Pediatrics, University of Oslo and Rikshospitalet, Oslo, Norway

    Tobias Gedde-Dahl Jr

  5. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Loverval, Belgium

    Lionel Van Maldergem

  6. Université Saint-Joseph, Faculté de Médecine, Unité de Génétique Médicale, Beyrouth, Lebanon

    André Mégarbané

  7. BSCL Working Group,

    BSCL Working Group

  8. Berardinelli–Seip Study Group, Belgium, Brazil, Czech Republic, France, Italy, The Netherlands, Norway, Portugal, South Africa, UK, USA

    BSCL Working Group

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  1. Jocelyne Magré
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Correspondence to Jocelyne Magré.

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Magré, J., Delépine, M., Khallouf, E. et al. Identification of the gene altered in Berardinelli–Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28, 365–370 (2001). https://doi.org/10.1038/ng585

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