Genentech Inc., South San Francisco, CA 94080, USA.
Cell. 2011 May 13;145(4):513-28. doi: 10.1016/j.cell.2011.04.019.
Nephronophthisis (NPHP), Joubert (JBTS), and Meckel-Gruber (MKS) syndromes are autosomal-recessive ciliopathies presenting with cystic kidneys, retinal degeneration, and cerebellar/neural tube malformation. Whether defects in kidney, retinal, or neural disease primarily involve ciliary, Hedgehog, or cell polarity pathways remains unclear. Using high-confidence proteomics, we identified 850 interactors copurifying with nine NPHP/JBTS/MKS proteins and discovered three connected modules: "NPHP1-4-8" functioning at the apical surface, "NPHP5-6" at centrosomes, and "MKS" linked to Hedgehog signaling. Assays for ciliogenesis and epithelial morphogenesis in 3D renal cultures link renal cystic disease to apical organization defects, whereas ciliary and Hedgehog pathway defects lead to retinal or neural deficits. Using 38 interactors as candidates, linkage and sequencing analysis of 250 patients identified ATXN10 and TCTN2 as new NPHP-JBTS genes, and our Tctn2 mouse knockout shows neural tube and Hedgehog signaling defects. Our study further illustrates the power of linking proteomic networks and human genetics to uncover critical disease pathways.
肾单位-肠管-睾丸（NPHP）、Joubert（JBTS）和Meckel-Gruber（MKS）综合征是常染色体隐性纤毛病，表现为囊性肾脏、视网膜变性和小脑/神经管畸形。肾脏、视网膜或神经疾病中的缺陷主要涉及纤毛、Hedgehog 或细胞极性途径尚不清楚。使用高可信度蛋白质组学，我们鉴定了 850 个与九个 NPHP/JBTS/MKS 蛋白共纯化的相互作用体，并发现了三个连接模块：“NPHP1-4-8”在顶表面起作用，“NPHP5-6”在中心体上，“MKS”与 Hedgehog 信号通路相连。在 3D 肾脏培养物中的纤毛发生和上皮形态发生测定中，肾脏囊性疾病与顶膜组织缺陷有关，而纤毛和 Hedgehog 通路缺陷导致视网膜或神经缺陷。使用 38 个相互作用体作为候选物，对 250 名患者的连锁和测序分析确定了 ATXN10 和 TCTN2 为新的 NPHP-JBTS 基因，我们的 Tctn2 小鼠敲除显示神经管和 Hedgehog 信号缺陷。我们的研究进一步说明了将蛋白质组网络和人类遗传学联系起来以揭示关键疾病途径的力量。
