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RESEARCH PRODUCT
Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility
Ludmila FrancescattoCatherine Guettier-bouttierJean-baptiste RivièreEvelyne MarinierOlivier GouletPhilippe GauchezAlexandre FabreYves RimetJean-pierre HugotAurélie BourchanyLaurence FaivreCatherine BadensArnauld DelarueEmmanuel GonzalesFrédéric HuetRaphaelle MaudinasArnaud BlanchardNicholas KatsanisCéline Brochier-armanetChristel Thauvin-robinetSabine SigaudyJulien ThevenonCaroline LacosteKarin MazodierAnge-line BruelEmmanuelle Ecochard-dugelayNicolas LévyCécile De LeusseMina KomutaGéraldine HeryYannis DuffourdJacques SarlesBertrand RoquelaureXavier StéphennePatrice BourgeoisPerciliz L. TanClothilde Estevesubject
0301 basic medicineDiarrheaMaleCandidate geneAdolescentBone fragilityArticleBone and Bones03 medical and health sciencesYoung AdultCholestasisLoss of Function MutationGCUNC-45MyosinGeneticsMedicineAnimalsHumansFamilyLymphocytes[ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human geneticsHearing LossGeneGenetics (clinical)Loss functionZebrafishCholestasisbusiness.industryInfant NewbornIntracellular Signaling Peptides and ProteinsSyndromeFibroblastsmedicine.disease3. Good healthPedigreeDiarrhea030104 developmental biologyPhenotype[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human geneticsConcomitantChild PreschoolImmunologyFemalemedicine.symptombusinessGastrointestinal Motilitydescription
International audience; Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-03-01 |