title: 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.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Alby
authors.affiliation: INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Piquand
authors.affiliation: INSERM U1163, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Huber
authors.affiliation: Medical Genetics Unit, Saint Joseph University, Rue de Damas, BP 175208, Mar Mikhaël, Beyrouth 1104, Lebanon.
authors.forename: André
authors.initials: A
authors.lastname: Megarbané
authors.affiliation: 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.
authors.forename: Amale
authors.initials: A
authors.lastname: Ichkou
authors.affiliation: Department of Genetics, Poitiers University Hospital, 2 Rue de la Milétrie, 86021 Poitiers, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Legendre
authors.affiliation: Unité de Pathologie Fœtoplacentaire, Groupe Hospitalier Pellegrin, Centre Hospitalier Universitaire, Place Amélie Raba-Léon, 33076 Bordeaux Cedex, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Pelluard
authors.affiliation: 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.
authors.forename: Ferechté
authors.initials: F
authors.lastname: Encha-Ravazi
authors.affiliation: Service de Gynécologie Obstétrique, Hôtel-Dieu de France, BP 166830, Achrafieh, Beyrouth 1100, Lebanon.
authors.forename: Georges
authors.initials: G
authors.lastname: Abi-Tayeh
authors.affiliation: Département de Génétique, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
authors.forename: Bettina
authors.initials: B
authors.lastname: Bessières
authors.affiliation: Génétique et Anomalies du Développement EA4271, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Salima
authors.initials: S
authors.lastname: El Chehadeh-Djebbar
authors.affiliation: Génétique et Anomalies du Développement EA4271, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Laurent
authors.affiliation: Génétique et Anomalies du Développement EA4271, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Szeged, Korányi fasor 14-15, 6725 Szeged, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Sztriha
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Szeged, Korányi fasor 14-15, 6725 Szeged, Hungary.
authors.forename: Melinda
authors.initials: M
authors.lastname: Zombor
authors.affiliation: Department of Paediatrics, Faculty of Medicine, University of Szeged, Korányi fasor 14-15, 6725 Szeged, Hungary.
authors.forename: Hajnalka
authors.initials: H
authors.lastname: Szabó
authors.affiliation: INSERM U1163, Laboratory of Inherited Kidney Diseases, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Failler
authors.affiliation: Cell Imaging Platform, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Garfa-Traore
authors.affiliation: Genomic Core Facility, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole
authors.affiliation: Bioinformatics Core Facility, Paris Descartes University, Sorbonne Paris Cité, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschké
authors.affiliation: 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.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Nizon
authors.affiliation: 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.
authors.forename: Nadia
authors.initials: N
authors.lastname: Elkhartoufi
authors.affiliation: INSERM U1163, Laboratory of Embryology and Genetics of Congenital Malformations, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Clerget-Darpoux
authors.affiliation: 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.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: 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.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.affiliation: 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.
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.affiliation: INSERM U1163, Laboratory of Inherited Kidney Diseases, Paris Descartes University, Sorbonne Paris Cité and Imagine Institute, 75015 Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Saunier
authors.affiliation: 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.
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.affiliation: 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.
authors.forename: Tania
authors.initials: T
authors.lastname: Attié-Bitach
authors.affiliation: 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002925:Ciliary Motility Disorders / Q000235:genetics* / Q000473:pathology; D018389:Codon, Nonsense / Q000235:genetics*; D005061:Europe, Eastern; D017809:Fatal Outcome; D018703:Founder Effect; D006228:Hand Deformities, Congenital / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics*; D016013:Likelihood Functions; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D018389:Codon, Nonsense; C587687:KIAA0586 protein, human