A role for Alström syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence.
A role for Alström syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence.
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DOI：
10.1371/journal.pgen.0030008
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发表时间：
2007-01-05
期刊：
影响因子：
4.5
通讯作者：
Glynne, Richard
中科院分区：
文献类型：
--
作者：
Li, Guochun;Vega, Raquel;Nelms, Keats;Gekakis, Nicholas;Goodnow, Christopher;McNamara, Peter;Wu, Hua;Hong, Nancy A.;Glynne, Richard
ALMS1 基因中的过早截断等位基因是人类阿尔斯特罗姆综合征的常见原因。阿尔斯特罗姆综合征是一种罕见的疾病，其特征是早期肥胖和感觉障碍，其症状与影响初级纤毛蛋白质的其他遗传病相同。 ALMS1 定位于中心体和纤毛基体，但 Alms1/ALMS1 的截短突变并不妨碍纤毛的形成。在这里，我们发现在小鼠中体外敲低 Alms1 会导致肾上皮细胞上的纤毛发育不良，并阻止这些细胞响应机械刺激而增加钙流入。纤毛发育不良表型可以用 Alms1 cDNA 的 5' 片段来挽救，该片段类似于疾病相关的等位基因。在 Alström 综合征小鼠模型中，Alms1 蛋白可以从突变等位基因中稳定表达，并且是原代细胞中纤毛形成所必需的。老年小鼠的肾近端小管纤毛发生了特定的损失，这与细胞凋亡或增殖灶有关。由于肾衰竭是阿尔斯特罗姆综合征患者死亡的常见原因，我们得出结论，这种疾病应被视为肾纤毛病类别的进一步例子：阿尔斯特罗姆综合征基因的野生型或突变等位基因可以在体外和体内支持正常的肾脏纤毛发生，但突变等位基因与年龄依赖性的肾脏初级纤毛丢失有关。 Alström 综合征是一种罕见的遗传性疾病，由 ALMS1 基因突变引起。该疾病的特点是失明、耳聋和代谢紊乱。这些症状让人想起影响初级纤毛的疾病，初级纤毛是一种细胞附属物，具有感知细胞外环境变化的作用。此外，肾衰竭是阿尔斯特罗姆综合征患者的常见死因，最近的研究表明原发纤毛缺陷与囊性肾病之间存在因果关系。在本文中，我们证明 ALMS1 蛋白是肾细胞中形成纤毛所必需的。该基因的突变等位基因与人类疾病中的突变等位基因相似，能够支持细胞培养物和动物中纤毛的形成。然而，在老年小鼠中发现了疾病等位基因的功能缺陷：肾细胞中纤毛丢失，这与细胞增殖和细胞死亡的增加有关。这些数据与纤毛发生中 ALMS1 的要求一致，并表明阿尔斯特罗姆综合征包含在不断增长的纤毛相关病理类别中。
Premature truncation alleles in the ALMS1 gene are a frequent cause of human Alström syndrome. Alström syndrome is a rare disorder characterized by early obesity and sensory impairment, symptoms shared with other genetic diseases affecting proteins of the primary cilium. ALMS1 localizes to centrosomes and ciliary basal bodies, but truncation mutations in Alms1/ALMS1 do not preclude formation of cilia. Here, we show that in vitro knockdown of Alms1 in mice causes stunted cilia on kidney epithelial cells and prevents these cells from increasing calcium influx in response to mechanical stimuli. The stunted-cilium phenotype can be rescued with a 5′ fragment of the Alms1 cDNA, which resembles disease-associated alleles. In a mouse model of Alström syndrome, Alms1 protein can be stably expressed from the mutant allele and is required for cilia formation in primary cells. Aged mice developed specific loss of cilia from the kidney proximal tubules, which is associated with foci of apoptosis or proliferation. As renal failure is a common cause of mortality in Alström syndrome patients, we conclude that this disease should be considered as a further example of the class of renal ciliopathies: wild-type or mutant alleles of the Alström syndrome gene can support normal kidney ciliogenesis in vitro and in vivo, but mutant alleles are associated with age-dependent loss of kidney primary cilia. Alström syndrome is a rare genetic disorder caused by mutations in the ALMS1 gene. The disease is characterized by blindness, deafness, and metabolic disorders. These symptoms are reminiscent of diseases affecting the primary cilium, a cellular appendage with a role in sensing changes to the extracellular environment. In addition, kidney failure is a frequent cause of death in Alström syndrome patients, and recent studies have suggested a causal relationship between defects in primary cilia and cystic kidney diseases. In this paper, we show that ALMS1 protein is required to form cilia in kidney cells. Mutant alleles of the gene that are similar to those seen in the human disease are able to support cilia formation in cell culture and in animals. However, a defect in the function of the disease alleles is uncovered in older mice: cilia are lost from the kidney cells, and this is associated with an increase in cellular proliferation and cell death. The data are consistent with a requirement for ALMS1 in ciliogenesis and suggest inclusion of Alström syndrome among the growing class of cilia-related pathologies.
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DOI：
10.1073/pnas.0402354101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Mykytyn, K;Mullins, RF;Sheffield, VC
通讯作者：
Sheffield, VC
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影响因子：
30.8
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Hearn, T;Renforth, GL;Wilson, DI
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Wilson, DI