Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes
Subcellular localization of ALMS1 supports involvement of centrosome and basal body dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes
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DOI：
10.2337/diabetes.54.5.1581
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发表时间：
2005-05-01
期刊：
影响因子：
7.7
通讯作者：
Wilson, DI
中科院分区：
文献类型：
--
作者：
Hearn, T;Spalluto, C;Wilson, DI
Alstrom综合征是一种罕见的常染色体隐性遗传病，由一种功能未知的新基因ALMS 1突变引起。Alstrom综合征的主要特征包括肥胖、胰岛素抵抗和2型糖尿病，因此研究ALMS 1功能有助于为这些常见疾病的发病机制提供新的见解。为了开始这一过程，我们分析了ALMS 1的亚细胞定位和组织分布的免疫荧光。我们发现，ALMS 1广泛表达，并定位于中心体和纤毛的基础。ALMS 1被破坏的成纤维细胞组装初级纤毛和微管细胞骨架，这些细胞骨架看起来正常，这表明Alstrom综合征表型是由功能受损而不是发育异常引起的。再加上最近关于Bardet-Biedl综合征复杂表型的数据，我们的研究结果暗示了基体和中心体功能障碍在肥胖、胰岛素抵抗和2型糖尿病发病机制中的意想不到的中心作用。揭示Alstrom综合征表型的分子机制对于寻找新的治疗靶点非常重要。
Alstrom syndrome is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1. Central features of Alstrom syndrome include obesity, insulin resistance, and type 2 diabetes, and therefore investigating ALMS1 function stands to offer new insights into the pathogenesis of these common conditions. To begin this process, we have analyzed the subcellular localization and tissue distribution of ALMS1 by immunofluorescence. We show that ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. Fibroblasts with disrupted ALMS1 assemble primary cilia and microtubule cytoskeletons that appear normal, suggesting that the Alstrom syndrome phenotype results from impaired function rather than abnormal development. Coupled with recent data on the complex phenotype of Bardet-Biedl syndrome, our findings imply an unexpected central role for basal body and centrosome dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Unraveling the molecular mechanisms underlying the Alstrom syndrome phenotype will be important in the search for new therapeutic targets for these conditions.