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
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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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    • "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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    ABSTRACT: Autism spectrum disorder is a neurodevelopmental disorder characterized by impairments in social interactions, reduced verbal communication abilities, stereotyped repetitive behaviors, and restricted interests. It is a complex condition caused by genetic and environmental factors; the high heritability of this disorder supports the presence of a significant genetic contribution. Many studies have suggested that copy-number variants contribute to the etiology of autism spectrum disorder. Recently, copy-number variants of the nephronophthisis 1 gene have been reported in patients with autism spectrum disorder. To the best of our knowledge, only six autism spectrum disorder cases with duplications of the nephronophthisis 1 gene have been reported. These patients exhibited intellectual dysfunction, including verbal dysfunction in one patient, below-average verbal intellectual ability in one patient, and intellectual disability in four patients. In this study, we identified nephronophthisis 1 duplications in two unrelated Japanese patients with autism spectrum disorder using a high-resolution single-nucleotide polymorphism array. This report is the first to describe a nephronophthisis 1 duplication in an autism spectrum disorder patient with an average verbal intelligence quotient and an average performance intelligence quotient. However, the second autism spectrum disorder patient with a nephronophthisis 1 duplication had a below-average performance intelligence quotient. Neither patient exhibited physical dysfunction, motor developmental delay, or neurological abnormalities. This study supports the clinical observation of nephronophthisis 1 duplication in autism spectrum disorder cases and might contribute to our understanding of the clinical phenotype that arises from this duplication.
    Annals of General Psychiatry 08/2014; 13(1):22. DOI:10.1186/s12991-014-0022-2 · 1.40 Impact Factor
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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.
    Cilia 06/2014; 4(Suppl 1). DOI:10.1016/j.celrep.2014.05.049
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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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    ABSTRACT: Primary cilia were the largely neglected nonmotile counterparts of their better-known cousin, the motile cilia. For years these nonmotile cilia were considered evolutionary remnants of little consequence to cellular function. Fast forward 10 years and we now recognize primary cilia as key integrators of extracellular ligand-based signaling and cellular polarity, which regulate neuronal cell fate, migration, differentiation, as well as a host of adult behaviors. Important future questions will focus on structure-function relationships, their roles in signaling and disease and as areas of target for treatments.
    Neuron 05/2014; 82(3):511-521. DOI:10.1016/j.neuron.2014.04.024 · 15.05 Impact Factor
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