Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
Nat Genet. 2010 Oct;42(10):840-50. doi: 10.1038/ng.662. Epub 2010 Sep 12.
Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.
肾单位-肠病相关纤毛病（NPHP-RC）是一种隐性疾病，其特征是肾、视网膜和小脑优先出现发育不良或退化。在这里，我们通过进行“纤毛病候选外显子捕获”并进行大规模平行测序，将纯合子作图与候选基因分析相结合。我们在 10 个受 NPHP-RC 影响的家庭中发现了 12 种不同的 SDCCAG8（血清定义的结肠癌抗原 8，也称为 CCCAP）截断突变。我们表明，SDCCAG8 定位于中心粒，并且与 OFD1（口腔面部数字综合征 1）直接相互作用，OFD1 与 NPHP-RC 相关。sdccag8 的缺失会导致斑马鱼的肾脏囊肿和身体轴缺陷，并在三维肾细胞培养物中诱导细胞极性缺陷。这项工作确定了 SDCCAG8 功能的丧失是视网膜-肾纤毛病的一个原因，并验证了外显子捕获分析在广泛的异质性单基因疾病中的应用。
