Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

  • Nat Genet. 2010 Oct;42(10):840-50. doi: 10.1038/ng.662.
Edgar A Otto  1 ,  Toby W Hurd ,  Rannar Airik ,  Moumita Chaki ,  Weibin Zhou ,  Corinne Stoetzel ,  Suresh B Patil ,  Shawn Levy ,  Amiya K Ghosh ,  Carlos A Murga-Zamalloa ,  Jeroen van Reeuwijk ,  Stef J F Letteboer ,  Liyun Sang ,  Rachel H Giles ,  Qin Liu ,  Karlien L M Coene ,  Alejandro Estrada-Cuzcano ,  Rob W J Collin ,  Heather M McLaughlin ,  Susanne Held ,  Jennifer M Kasanuki ,  Gokul Ramaswami ,  Jinny Conte ,  Irma Lopez ,  Joseph Washburn ,  James Macdonald ,  Jinghua Hu ,  Yukiko Yamashita ,  Eamonn R Maher ,  Lisa M Guay-Woodford ,  Hartmut P H Neumann ,  Nicholas Obermüller ,  Robert K Koenekoop ,  Carsten Bergmann ,  Xiaoshu Bei ,  Richard A Lewis ,  Nicholas Katsanis ,  Vanda Lopes ,  David S Williams ,  Robert H Lyons ,  Chi V Dang ,  Daniela A Brito ,  Mónica Bettencourt Dias ,  Xinmin Zhang ,  James D Cavalcoli ,  Gudrun Nürnberg ,  Peter Nürnberg ,  Eric A Pierce ,  Peter K Jackson ,  Corinne Antignac ,  Sophie Saunier ,  Ronald Roepman ,  Helene Dollfus ,  Hemant Khanna ,  Friedhelm Hildebrandt
Affiliations
  • 1. Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan, USA.
PMID: 20835237 DOI: 10.1038/ng.662
Abstract

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.