1. Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.
- Author
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Alby C, Piquand K, Huber C, Megarbané A, Ichkou A, Legendre M, Pelluard F, Encha-Ravazi F, Abi-Tayeh G, Bessières B, El Chehadeh-Djebbar S, Laurent N, Faivre L, Sztriha L, Zombor M, Szabó H, Failler M, Garfa-Traore M, Bole C, Nitschké P, Nizon M, Elkhartoufi N, Clerget-Darpoux F, Munnich A, Lyonnet S, Vekemans M, Saunier S, Cormier-Daire V, Attié-Bitach T, and Thomas S
- Subjects
- Base Sequence, Ciliary Motility Disorders pathology, Europe, Eastern, Fatal Outcome, Founder Effect, Humans, Likelihood Functions, Molecular Sequence Data, Pedigree, Sequence Analysis, DNA, Cell Cycle Proteins genetics, Ciliary Motility Disorders genetics, Codon, Nonsense genetics, Hand Deformities, Congenital genetics, Heart Defects, Congenital genetics, Hydrocephalus genetics, Phenotype, Short Rib-Polydactyly Syndrome genetics
- Abstract
KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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