Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy
Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy
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DOI：
10.1210/jc.2007-1328
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发表时间：
2008-04-01
影响因子：
5.8
通讯作者：
Magre, Jocelyne
中科院分区：
文献类型：
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作者：
Kim, C. A.;Delepine, Marc;Magre, Jocelyne
背景：贝拉尔迪内利 - 塞普先天性脂肪营养不良（BSCL）是一种罕见的隐性疾病，其特征是几乎没有脂肪组织，导致严重的血脂异常和胰岛素抵抗。在大多数已报道的病例中，BSCL是由于功能未知的塞平蛋白或1 - 酰基甘油 - 3 - 磷酸酰基转移酶 - β（AGPAT2）发生改变所致，AGPAT2催化磷脂酸的形成。
目的：我们试图确定无法解释的BSCL病例的遗传起源。因此，我们对编码小窝蛋白 - 1的CAV1进行测序，将其作为参与胰岛素信号传导和脂质内稳态的候选基因。CAV1是质膜小窝的关键结构成分，缺乏Cav1的小鼠表现出脂肪组织逐渐减少和胰岛素抵抗。
设计：我们对4名在编码塞平蛋白或AGPAT2的基因中无突变的BSCL患者进行了表型研究和CAV1的分子筛查。
结果：在一名近亲结婚所生育的BSCL患者的CAV1中发现了一个纯合无义突变（p.Glu38X）。该突变影响α - 和β - CAV1异构体，并消除皮肤成纤维细胞中CAV1的表达。对先证者进行的详细磁共振成像证实，皮下和内脏脂肪组织几乎完全缺失，仅在背部皮下区域有少量残留。与缺乏脂肪组织一致，先证者也有严重的胰岛素抵抗和血脂异常。此外，先证者有轻度低钙血症，可能是由于维生素D抵抗。
结论：这些发现确定CAV1是一个新的与BSCL相关的基因，并支持小窝蛋白在人类脂肪细胞功能中起关键作用。
Context: Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue, resulting in severe dyslipidemia and insulin resistance. In most reported cases, BSCL is due to alterations in either seipin, of unknown function, or 1-acylglycerol-3- phosphate acyltransferase-beta (AGPAT2), which catalyzes the formation of phosphatidic acid.Objective: We sought to determine the genetic origin of the unexplained cases of BSCL. We thus sequenced CAV1, encoding caveolin-1, as a candidate gene involved in insulin signaling and lipid homeostasis. CAV1 is a key structural component of plasma membrane caveolae, and Cav1-deficient mice display progressive loss of adipose tissue and insulin resistance.Design: We undertook phenotyping studies and molecular screening of CAV1 in four patients with BSCL with no mutation in the genes encoding either seipin or AGPAT2.Results: A homozygous nonsense mutation (p.Glu38X) was identified in CAV1 in a patient with BSCL born from a consanguineous union. This mutation affects both the alpha-and beta-CAV1 isoforms and ablates CAV1 expression in skin fibroblasts. Detailed magnetic resonance imaging of the proband confirmed near total absence of both sc and visceral adipose tissue, with only vestigial amounts in the dorsal sc regions. In keeping with the lack of adipose tissue, the proband was also severely insulin resistant and dyslipidemic. In addition, the proband had mild hypocalcemia likely due to vitamin D resistance.Conclusions: These findings identify CAV1 as a new BSCL-related gene and support a critical role for caveolins in human adipocyte function.