Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13
Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13
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DOI：
10.1038/ng585
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发表时间：
2001-08-01
期刊：
影响因子：
30.8
通讯作者：
Capeau, J
中科院分区：
文献类型：
--
作者：
Magré, J;Delépine, M;Capeau, J
先天性全身性脂肪营养不良或Berardinelli-Seip综合征（BSCL）是一种罕见的常染色体隐性遗传疾病，其特征是出生或婴儿早期几乎没有脂肪组织和严重的胰岛素抵抗（1-4）。其他临床和生物学特征包括黑棘皮病、高雄激素血症、肌肉肥大、肝肿大、葡萄糖耐量改变或糖尿病和高胆固醇血症。一个基因座（BSCL 1）已被定位到9 q34，有异质性的证据（5）。在这里，我们报告了来自两个地理集群（黎巴嫩和挪威）的9个BSCL家族的基因组筛选。我们确定了一个新的疾病位点，命名为BSCL 2，在2.5 Mb的间隔两侧的标记D11 S4076和D11 S480的染色体11 q13。分析了20个不同种族的家庭，确定了11个家庭，其中疾病与11 q13基因座共分离，其余的家庭提供确认的连锁9 q34。位于11 q13区间的基因序列分析揭示了所有BSCL 2连锁家族中与鼠鸟嘌呤核苷酸结合蛋白（G蛋白），γ 3连锁基因（6）（Gng 3lg）同源的基因突变。BSCL 2在大脑和睾丸中表达最高，编码一种功能未知的蛋白质（我们称之为seipin）。大多数变体是无效突变，可能导致蛋白质的严重破坏。这些发现对于了解体脂分布和胰岛素抵抗的分子机制具有重要意义。
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(1-4). 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 heterogeneity(5). 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(6) (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.