Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome.

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.

• Authors: Caroline Alby, Kevin Piquand, Céline Huber, André Megarbané, Amale Ichkou, Marine Legendre, Fanny Pelluard, Ferechté Encha-Ravazi, Georges Abi-Tayeh, Bettina Bessières, Salima El Chehadeh-Djebbar, Nicole Laurent, Laurence Faivre, László Sztriha, Melinda Zombor, Hajnalka Szabó, Marion Failler, Meriem Garfa-Traore, Christine Bole, Patrick Nitschké, Mathilde Nizon, Nadia Elkhartoufi, Françoise Clerget-Darpoux, Arnold Munnich, Stanislas Lyonnet, Michel Vekemans, Sophie Saunier, Valérie Cormier-Daire, Tania Attié-Bitach, Sophie Thomas
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 97 Issue 2 Pg. 311-8 (Aug 06 2015) ISSN: 1537-6605 [Electronic] United States
• PMID: 26166481 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Codon, Nonsense
• KIAA0586 protein, human

Topics

• Base Sequence
• Cell Cycle Proteins (genetics)
• Ciliary Motility Disorders (genetics, pathology)
• Codon, Nonsense (genetics)
• Europe, Eastern
• Fatal Outcome
• Founder Effect
• Hand Deformities, Congenital (genetics)
• Heart Defects, Congenital (genetics)
• Humans
• Hydrocephalus (genetics)
• Likelihood Functions
• Molecular Sequence Data
• Pedigree
• Phenotype
• Sequence Analysis, DNA
• Short Rib-Polydactyly Syndrome (genetics)