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

Otto, E.A., Hurd, T.W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S.B., Levy, S., Ghosh, A.K., Murga-Zamalloa, C.A., van Reeuwijk, J., Letteboer, S.J., Sang, L., Giles, R.H., Liu, Q., Coene, K.L., Estrada-Cuzcano, A., Collin, R.W., McLaughlin, H.M., Held, S., Kasanuki, J.M., Ramaswami, G., Conte, J., Lopez, I., Washburn, J., Macdonald, J., Hu, J., Yamashita, Y., Maher, E.R., Guay-Woodford, L.M., Neumann, H.P., Obermüller, N., Koenekoop, R.K., Bergmann, C., Bei, X., Lewis, R.A., Katsanis, N., Lopes, V., Williams, D.S., Lyons, R.H., Dang, C.V., Brito, D.A., Dias, M.B., Zhang, X., Cavalcoli, J.D., Nürnberg, G., Nürnberg, P., Pierce, E.A., Jackson, P.K., Antignac, C., Saunier, S., Roepman, R., Dollfus, H., Khanna, H., and Hildebrandt, F.
Nature Genetics   42(10): 840-850 (Journal)
Registered Authors
Katsanis, Nicholas, Khanna, Hemant, Liu, Qin, Zhou, Weibin
MeSH Terms
  • Animals
  • Autoantigens/genetics*
  • Blotting, Western
  • Case-Control Studies
  • Centrosome/metabolism
  • Cyclic AMP/metabolism
  • Exons/genetics*
  • Family
  • Fluorescent Antibody Technique, Indirect
  • Gene Expression Regulation, Developmental
  • Genetic Association Studies*
  • Homozygote
  • Humans
  • Kidney Diseases/genetics*
  • Kidney Diseases/pathology
  • Mice
  • Molecular Sequence Data
  • Mutation/genetics*
  • Neoplasm Proteins/antagonists & inhibitors
  • Neoplasm Proteins/genetics*
  • Photoreceptor Cells, Vertebrate/metabolism
  • Photoreceptor Cells, Vertebrate/ultrastructure
  • Proteins/genetics
  • Proteins/metabolism
  • RNA, Messenger/genetics
  • RNA, Small Interfering/pharmacology
  • Rats
  • Retinal Diseases/genetics*
  • Retinal Diseases/pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Subcellular Fractions
  • Two-Hybrid System Techniques
  • Zebrafish/genetics
  • Zebrafish/growth & development
20835237 Full text @ Nat. Genet.
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.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes