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.

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The presence of circulating adiponectin in BSCL2/seipin patients with near absence of adipose tissue outlines the complexity of adiponectin biology. Use of circulating adiponectin might be helpful to guide the genetic investigations in BSCL.

Congenital generalized lipoatrophy (CGL) is a syndrome with multiple clinical manifestations and complete atrophy of adipose tissue. The exact mechanism of this disease remains unknown. One hypothesis presupposes an abnormal development of adipocytes. Leptin, the adipocyte-specific product of the ob gene, acts as a regulatory factor of body weight. In children, as in adults, leptin levels are correlated with body mass index (BMI) and body fat mass. Some authors have demonstrated that adults with congenital or acquired generalized lipoatrophy have decreased leptin concentrations. In order to study serum leptin profile during childhood in this disease, we measured serum leptin concentrations in six children aged 5.5-11 years suffering from CGL, and investigated the relationship between metabolic parameters and the variations in leptin levels. Serum leptin concentrations (1.19 Ϯ 0.32 ng/ml (Ϯ S.D.)) were extremely low compared with those observed in normal children. No significant correlation was found with BMI, which is known to be one of the major determinants of serum leptin. Serum leptin values were significantly correlated with fasting insulin levels (r ¼ 0:83, P ¼ 0:024). In conclusion, extremely low leptin values measured in children with CGL could be regarded as one among other diagnostic parameters. However, the detectable levels observed in all of these children support the evidence that a small amount of body fat is likely to be present in these patients, despite complete subcutaneous lipoatrophy. Our data suggest that this small amount of adipose tissue could be metabolically active and, at least in part, sensitive to insulin. Further investigations are required to uncover the pathophysiological mechanisms of this syndrome, known to be commonly associated with insulin resistance.