1. Mutation of POC1B in a severe syndromic retinal ciliopathy.
- Author
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Beck BB, Phillips JB, Bartram MP, Wegner J, Thoenes M, Pannes A, Sampson J, Heller R, Göbel H, Koerber F, Neugebauer A, Hedergott A, Nürnberg G, Nürnberg P, Thiele H, Altmüller J, Toliat MR, Staubach S, Boycott KM, Valente EM, Janecke AR, Eisenberger T, Bergmann C, Tebbe L, Wang Y, Wu Y, Fry AM, Westerfield M, Wolfrum U, and Bolz HJ
- Subjects
- Abnormalities, Multiple, Amino Acid Motifs, Amino Acid Sequence, Animals, Cell Cycle Proteins metabolism, Cerebellar Diseases metabolism, Cerebellar Diseases pathology, Cerebellum abnormalities, Child, Cilia metabolism, Cilia ultrastructure, Eye Abnormalities metabolism, Eye Abnormalities pathology, Gene Knockdown Techniques, Humans, Iraq, Kidney pathology, Kidney Diseases, Cystic metabolism, Kidney Diseases, Cystic pathology, Leber Congenital Amaurosis genetics, Leber Congenital Amaurosis metabolism, Male, Mice, Molecular Sequence Data, Pedigree, Retina metabolism, Retina pathology, Zebrafish, Cell Cycle Proteins genetics, Cerebellar Diseases genetics, Eye Abnormalities genetics, Kidney Diseases, Cystic genetics, Mutation, Retina abnormalities
- Abstract
We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next-generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD., (© 2014 WILEY PERIODICALS, INC.)
- Published
- 2014
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