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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.

SUBMITTER: Alby C 

PROVIDER: S-EPMC4573270 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Alby Caroline C   Piquand Kevin K   Huber Céline C   Megarbané André A   Ichkou Amale A   Legendre Marine M   Pelluard Fanny F   Encha-Ravazi Ferechté F   Abi-Tayeh Georges G   Bessières Bettina B   El Chehadeh-Djebbar Salima S   Laurent Nicole N   Faivre Laurence L   Sztriha László L   Zombor Melinda M   Szabó Hajnalka H   Failler Marion M   Garfa-Traore Meriem M   Bole Christine C   Nitschké Patrick P   Nizon Mathilde M   Elkhartoufi Nadia N   Clerget-Darpoux Françoise F   Munnich Arnold A   Lyonnet Stanislas S   Vekemans Michel M   Saunier Sophie S   Cormier-Daire Valérie V   Attié-Bitach Tania T   Thomas Sophie S  

American journal of human genetics 20150709 2


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 wel  ...[more]

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