Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell

Genentech Inc., South San Francisco, CA 94080, USA.
Cell (Impact Factor: 32.24). 05/2011; 145(4):513-28. DOI: 10.1016/j.cell.2011.04.019
Source: PubMed


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.

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Available from: Jeremy F Reiter
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    • "The NPHP1 gene and its product are associated with the primary cilium and basal body (PC/BB) and subcellular organelles [15]. The PC/BB control diverse cellular processes such as cell division, differentiation, migration, and planar cell polarity through signaling pathways [11],[15]. These molecular findings and reports of the clinical phenotypes in patients with an altered NPHP1 gene support the hypothesis that the gene is associated with brain development and cognitive impairment. "
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    • "B9 domains are ciliary C2 domains that are not expected to bind Ca 2+ and are present in nearly all ciliated organisms (Bialas et al., 2009; Zhang and Aravind, 2010). Furthermore, the MKS-associated protein CC2D2A (= MKS6) and the Joubert-linked protein AhiI are predicted to possess C2 domains as well (Sang et al., 2011; Zhang and Aravind, 2012). Yeast-two-hybrid experiments have shown that the C2C domains of both RPGRIP1 and RPGRIP1L interact with NPHP4, and in vitro pull-downs further demonstrated that the interaction between the C2C of RPGRIP1 and NPHP4 is Ca 2+ independent (Roepman et al., 2005). "
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    ABSTRACT: RPGR-interacting protein 1 (RPGRIP1) is mutated in the eye disease Leber congenital amaurosis (LCA) and its structural homolog, RPGRIP1-like (RPGRIP1L), is mutated in many different ciliopathies. Both are multidomain proteins that are predicted to interact with retinitis pigmentosa G-protein regulator (RPGR). RPGR is mutated in X-linked retinitis pigmentosa and is located in photoreceptors and primary cilia. We solved the crystal structure of the complex between the RPGR-interacting domain (RID) of RPGRIP1 and RPGR and demonstrate that RPGRIP1L binds to RPGR similarly. RPGRIP1 binding to RPGR affects the interaction with PDEδ, the cargo shuttling factor for prenylated ciliary proteins. RPGRIP1-RID is a C2 domain with a canonical β sandwich structure that does not bind Ca(2+) and/or phospholipids and thus constitutes a unique type of protein-protein interaction module. Judging from the large number of C2 domains in most of the ciliary transition zone proteins identified thus far, the structure presented here seems to constitute a cilia-specific module that is present in multiprotein transition zone complexes.
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    • "Furthermore, when these truncated cDNAs are transfected into cells there is inhibition of ciliogenesis , suggesting SCA may relate to ciliary defects. Ataxin10, displaying a trinucleotide expansion as the cause for spinocerebellar ataxia-10 (SCA10), showed a homozygous splice mutation in a patient with JBTS (Sang et al., 2011). These examples suggest a potential connection between cerebellar development and degeneration linked by cilia but will require specific human alleles introduced into in vivo models to clarify these links. "
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