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Mutations in <i>MAPKBP1</i> Cause Juvenile or Late-Onset Cilia-Independent Nephronophthisis
Macia, Maxence S.,Halbritter, Jan,Delous, Marion,Bredrup, Cecilie,Gutter, Arthur,Filhol, Emilie,Mellgren, Anne E.C.,Leh, Sabine,Bizet, Albane,Braun, Daniela A.,Gee, Heon Y.,Silbermann, Flora,Henry, Ch University of Chicago Press [etc.] 2017 American journal of human genetics Vol.100 No.2
<P>Nephronophthisis (NPH), an autosomal-recessive tubulointerstitial nephritis, is the most common cause of hereditary end-stage renal disease in the first three decades of life. Since most NPH gene products (NPHP) function at the primary cilium, NPH is classified as a ciliopathy. We identified mutations in a candidate gene in eight individuals from five families presenting late-onset NPH with massive renal fibrosis. This gene encodes MAPKBP1, a poorly characterized scaffolding protein for JNK signaling. Immunofluorescence analyses showed that MAPKBP1 is not present at the primary cilium and that fibroblasts from affected individuals did not display ciliogenesis defects, indicating that MAPKBP1 may represent a new family of NPHP not involved in cilia-associated functions. Instead, MAPKBP1 is recruited to mitotic spindle poles (MSPs) during the early phases of mitosis where it colocalizes with its paralog WDR62, which plays a key role at MSP. Detected mutations compromise recruitment of MAPKBP1 to the MSP and/or its interaction with JNK2 or WDR62. Additionally, we show increased DNA damage response signaling in fibroblasts from affected individuals and upon knockdown of <I>Mapkbp1</I> in murine cell lines, a phenotype previously associated with NPH. In conclusion, we identified mutations in <I>MAPKBP1</I> as a genetic cause of juvenile or late-onset and cilia-independent NPH.</P>
Mutations of CEP83 Cause Infantile Nephronophthisis and Intellectual Disability
Failler, M.,Gee, H.,Krug, P.,Joo, K.,Halbritter, J.,Belkacem, L.,Filhol, E.,Porath, Jonathan D.,Braun, Daniela A.,Schueler, M.,Frigo, A.,Alibeu, O.,Masson, C.,Brochard, K.,Hurault de Ligny, B.,Novo, R University of Chicago Press [etc.] 2014 American journal of human genetics Vol.94 No.6
Ciliopathies are a group of hereditary disorders associated with defects in cilia structure and function. The distal appendages (DAPs) of centrioles are involved in the docking and anchoring of the mother centriole to the cellular membrane during ciliogenesis. The molecular composition of DAPs was recently elucidated and mutations in two genes encoding DAPs components (CEP164/NPHP15, SCLT1) have been associated with human ciliopathies, namely nephronophthisis and orofaciodigital syndrome. To identify additional DAP components defective in ciliopathies, we independently performed targeted exon sequencing of 1,221 genes associated with cilia and 5 known DAP protein-encoding genes in 1,255 individuals with a nephronophthisis-related ciliopathy. We thereby detected biallelic mutations in a key component of DAP-encoding gene, CEP83, in seven families. All affected individuals had early-onset nephronophthisis and four out of eight displayed learning disability and/or hydrocephalus. Fibroblasts and tubular renal cells from affected individuals showed an altered DAP composition and ciliary defects. In summary, we have identified mutations in CEP83, another DAP-component-encoding gene, as a cause of infantile nephronophthisis associated with central nervous system abnormalities in half of the individuals.