title: Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.
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 resistance. 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 heterogeneity. 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), gamma3-linked gene (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.
authors.affiliation: INSERM U.402, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, 27 rue Chaligny, 75012 Paris, France. magre@st-antoine.inserm.fr
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mesh_terms: D000052:Acanthosis Nigricans / Q000150:complications; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016000:Cluster Analysis; D004252:DNA Mutational Analysis; D048909:Diabetes Complications; D005260:Female; D044388:GTP-Binding Protein gamma Subunits; D005808:Genes, Recessive; D008040:Genetic Linkage; D005819:Genetic Markers; D005820:Genetic Testing; D006239:Haplotypes; D006529:Hepatomegaly / Q000150:complications; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D017588:Hyperandrogenism / Q000150:complications; D015228:Hypertriglyceridemia / Q000150:complications; D007333:Insulin Resistance / Q000235:genetics; D007861:Lebanon / Q000453:epidemiology; D008060:Lipodystrophy / Q000150:complications / Q000151:congenital* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009664:Norway / Q000453:epidemiology; D009928:Organ Specificity; D010375:Pedigree; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: C432679:BSCL2 protein, human; C115783:Bscl2 protein, mouse; D044388:GTP-Binding Protein gamma Subunits; D005819:Genetic Markers; D011506:Proteins; D020962:Heterotrimeric GTP-Binding Proteins