6533b860fe1ef96bd12c2fcb
RESEARCH PRODUCT
Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome
Kevin PiquandNadia ElkhartoufiNadia ElkhartoufiPatrick NitschkeSophie SaunierMeriem Garfa-traoreMathilde NizonMathilde NizonCaroline AlbyCaroline AlbyCéline HuberMarine LegendreBettina BessièresFrançoise Clerget-darpouxValérie Cormier-daireValérie Cormier-daireFanny PelluardFerechté Encha-ravaziFerechté Encha-ravaziArnold MunnichArnold MunnichAndré MégarbanéNicole LaurentTania Attié-bitachTania Attié-bitachSalima El Chehadeh-djebbarMelinda ZomborSophie ThomasGeorges Abi-tayehLaurence FaivreAmale IchkouAmale IchkouMichel VekemansMichel VekemansHajnalka SzabóChristine BoleMarion FaillerStanislas LyonnetStanislas LyonnetLászló Sztrihasubject
Heart Defects CongenitalMolecular Sequence DataCell Cycle ProteinsBiologyShort Rib-Polydactyly SyndromeCiliopathies03 medical and health sciencesFatal OutcomeCiliogenesisReportGLI3GeneticsmedicineHumansGenetics(clinical)Europe EasternGenetics (clinical)030304 developmental biologyGenetics0303 health sciencesLikelihood FunctionsShort rib – polydactyly syndromePolydactylyBase SequenceCilium030305 genetics & hereditySequence Analysis DNAmedicine.diseasePhenotypeHuman geneticsHedgehog signaling pathwayFounder EffectPedigreePhenotypeCodon NonsenseCentriolar satelliteErratumHand Deformities CongenitalCiliary Motility DisordersHydrocephalusdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-08-01 |