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

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

Author information

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.

PMID:
26166481
PMCID:
PMC4573270
DOI:
10.1016/j.ajhg.2015.06.003
[Indexed for MEDLINE]
Free PMC Article

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