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

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

doi:10.1016/j.ajhg.2015.06.003

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

Am J Hum Genet. 2015 Aug 6;97(2):311-8. doi: 10.1016/j.ajhg.2015.06.003. Epub 2015 Jul 9.

Authors

Caroline Alby¹, Kevin Piquand², Céline Huber³, André Megarbané⁴, Amale Ichkou¹, Marine Legendre⁵, Fanny Pelluard⁶, Ferechté Encha-Ravazi¹, Georges Abi-Tayeh⁷, Bettina Bessières⁸, Salima El Chehadeh-Djebbar⁹, Nicole Laurent⁹, Laurence Faivre⁹, László Sztriha¹⁰, Melinda Zombor¹⁰, Hajnalka Szabó¹⁰, Marion Failler¹¹, Meriem Garfa-Traore¹², Christine Bole¹³, Patrick Nitschké¹⁴, Mathilde Nizon¹⁵, Nadia Elkhartoufi¹, Françoise Clerget-Darpoux², Arnold Munnich¹, Stanislas Lyonnet¹, Michel Vekemans¹, Sophie Saunier¹¹, Valérie Cormier-Daire¹⁵, Tania Attié-Bitach¹, Sophie Thomas¹⁶

Affiliations

¹ INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France; Département de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
² INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
³ INSERM U1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
⁴ Medical Genetics Unit, Saint Joseph University, Rue de Damas, BP 175208, Mar Mikhaël, Beyrouth 1104, Lebanon.
⁵ Department of Genetics, Poitiers University Hospital, 2 Rue de la Milétrie, 86021 Poitiers, France.
⁶ Unité de Pathologie Fœtoplacentaire, Groupe Hospitalier Pellegrin, Centre Hospitalier Universitaire, Place Amélie Raba-Léon, 33076 Bordeaux Cedex, France.
⁷ Service de Gynécologie Obstétrique, Hôtel-Dieu de France, BP 166830, Achrafieh, Beyrouth 1100, Lebanon.
⁸ Département de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
⁹ Génétique et Anomalies du Développement EA4271, Université de Bourgogne, 21000 Dijon, France.
¹⁰ Department of Paediatrics, Faculty of Medicine, University of Szeged, Korányi fasor 14-15, 6725 Szeged, Hungary.
¹¹ INSERM U1163, Laboratory of Inherited Kidney Diseases, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
¹² Cell Imaging Platform, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
¹³ Genomic Core Facility, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
¹⁴ Bioinformatics Core Facility, Paris Descartes University, Sorbonne Paris Cité, 75015 Paris, France.
¹⁵ Département de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France; INSERM U1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
¹⁶ INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France. Electronic address: sophie.thomas@inserm.fr.

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.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Base Sequence
Cell Cycle Proteins / genetics*
Ciliary Motility Disorders / genetics*
Ciliary Motility Disorders / 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*

Substances

Cell Cycle Proteins
Codon, Nonsense
KIAA0586 protein, human

Supplementary concepts

Hydrolethalus syndrome