Cook Susan A, Collin Gayle B, Bronson Roderick T, Naggert Jürgen K, Liu Dong P, Akeson Ellen C, Davisson Muriel T
The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
J Am Soc Nephrol. 2009 Apr;20(4):753-64. doi: 10.1681/ASN.2008040412. Epub 2009 Feb 11.
Meckel-Gruber syndrome type 3 (MKS3; OMIM 607361) is a severe autosomal recessive disorder characterized by bilateral polycystic kidney disease. Other malformations associated with MKS3 include cystic changes in the liver, polydactyly, and brain abnormalities (occipital encephalocele, hydrocephalus, and Dandy Walker-type cerebellar anomalies). The disorder is hypothesized to be caused by defects in primary cilia. In humans, the underlying mutated gene, TMEM67, encodes transmembrane protein 67, also called meckelin (OMIM 609884), which is an integral protein of the renal epithelial cell and membrane of the primary cilium. Here, we describe a spontaneous deletion of the mouse ortholog, Tmem67, which results in polycystic kidney disease and death by 3 wk after birth. Hydrocephalus also occurs in some mutants. We verified the mutated gene by transgenic rescue and characterized the phenotype with microcomputed tomography, histology, scanning electron microscopy, and immunohistochemistry. This mutant provides a mouse model for MKS3 and adds to the growing set of mammalian models essential for studying the role of the primary cilium in kidney function.
3型梅克尔-格鲁伯综合征（MKS3；OMIM 607361）是一种严重的常染色体隐性疾病，其特征为双侧多囊肾病。与MKS3相关的其他畸形包括肝脏囊性改变、多指畸形以及脑部异常（枕部脑膨出、脑积水和丹迪-沃克型小脑异常）。据推测，该疾病是由原发性纤毛缺陷引起的。在人类中，潜在的突变基因TMEM67编码跨膜蛋白67，也称为梅克尔蛋白（OMIM 609884），它是肾上皮细胞和原发性纤毛膜的整合蛋白。在此，我们描述了小鼠直系同源基因Tmem67的自发缺失，这导致了多囊肾病并在出生后3周内死亡。一些突变体还出现了脑积水。我们通过转基因拯救验证了突变基因，并用微型计算机断层扫描、组织学、扫描电子显微镜和免疫组织化学对表型进行了表征。该突变体为MKS3提供了一个小鼠模型，并增加了越来越多的哺乳动物模型，这些模型对于研究原发性纤毛在肾功能中的作用至关重要。
