Alms1-disrupted mice recapitulate human Alstrom syndrome
Alms1-disrupted mice recapitulate human Alstrom syndrome
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DOI：
10.1093/hmg/ddi235
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发表时间：
2005-08-15
影响因子：
3.5
通讯作者：
Naggert, JK
中科院分区：
文献类型：
--
作者：
Collin, GB;Cyr, E;Naggert, JK
人ALMS 1基因突变导致Alstrom综合征（AS），这是一种以神经感觉缺陷和代谢缺陷（包括儿童肥胖、高胰岛素血症和2型糖尿病）为特征的进行性疾病。其他表现力变化更大的特征包括扩张型心肌病、高胆固醇血症、脊柱侧凸、发育迟缓以及肺和泌尿系统功能障碍。ALMS 1编码一种广泛表达的未知功能蛋白。为了获得一个动物模型，其中所观察到的病理的病因学可以进一步研究，我们产生了一个小鼠模型，使用Alms 1基因捕获的ES细胞系。Alms 1（-/-）小鼠出现与AS患者相似的特征，包括肥胖、性腺功能减退、高胰岛素血症、视网膜功能障碍和迟发性听力损失。胰岛素抵抗和体重增加在8至12周龄之间明显，高血糖症在16周龄时表现出来。此外，Alms 1（-/-）小鼠在8个月大之前听力正常，之后它们显示出异常的听觉脑干反应。早期观察到锥状ERG b波反应减弱，随后是感光细胞变性。电子显微镜显示积累的细胞内囊泡的光感受器的内段，而免疫组化分析显示错误定位的视紫红质的外核层。这些发现表明ALMS 1在细胞内运输中具有作用。
Mutations in the human ALMS1 gene cause Alstrom syndrome (AS), a progressive disease characterized by neurosensory deficits and by metabolic defects including childhood obesity, hyperinsulinemia and Type 2 diabetes. Other features that are more variable in expressivity include dilated cardiomyopathy, hypertriglyceridemia, hypercholesterolemia, scoliosis, developmental delay and pulmonary and urological dysfunctions. ALMS1 encodes a ubiquitously expressed protein of unknown function. To obtain an animal model in which the etiology of the observed pathologies could be further studied, we generated a mouse model using an Alms1 gene-trapped ES cell line. Alms1(-/-) mice develop features similar to patients with AS, including obesity, hypogonadism, hyperinsulinemia, retinal dysfunction and late-onset hearing loss. Insulin resistance and increased body weight are apparent between 8 and 12 weeks of age, with hyperglycemia manifesting at 16 weeks of age. In addition, Alms1(-/-) mice have normal hearing until 8 months of age, after which they display abnormal auditory brainstem responses. Diminished cone ERG b-wave response is observed early, followed by the degeneration of photoreceptor cells. Electron microscopy revealed accumulation of intracellular vesicles in the inner segments of photoreceptors, whereas immunohistochemical analysis showed mislocalization of rhodopsin to the outer nuclear layer. These findings suggest that ALMS1 has a role in intracellular trafficking.