2024
A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders
Lee A, Ayers L, Kosicki M, Chan W, Fozo L, Pratt B, Collins T, Zhao B, Rose M, Sanchis-Juan A, Fu J, Wong I, Zhao X, Tenney A, Lee C, Laricchia K, Barry B, Bradford V, Jurgens J, England E, Lek M, MacArthur D, Lee E, Talkowski M, Brand H, Pennacchio L, Engle E. A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders. Nature Communications 2024, 15: 8268. PMID: 39333082, PMCID: PMC11436875, DOI: 10.1038/s41467-024-52463-7.Peer-Reviewed Original ResearchConceptsNon-coding variantsCranial motor neuronsMendelian disordersIn vivo transgenic assayPredictor of enhancer activityCis-regulatory elementsMulti-omic frameworkWhole-genome sequencingEnhanced activityVariant discoveryGenome sequenceChromatin accessibilityPutative enhancersHistone modificationsRegulatory elementsGene expression assaysGene predictionTransgenic assaysEpigenomic profilingMendelian casesExpression assaysMutational enhancementCongenital cranial dysinnervation disordersCell typesFunctional impactGlis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Zhang C, Rehman M, Tian X, Pei S, Gu J, Bell T, Dong K, Tham M, Cai Y, Wei Z, Behrens F, Jetten A, Zhao H, Lek M, Somlo S. Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease. Nature Communications 2024, 15: 3698. PMID: 38693102, PMCID: PMC11063051, DOI: 10.1038/s41467-024-48025-6.Peer-Reviewed Original ResearchConceptsMouse models of autosomal dominant polycystic kidney diseaseModel of autosomal dominant polycystic kidney diseasePolycystin signalingAutosomal dominant polycystic kidney diseasePolycystin-1Polycystic kidney diseaseTreat autosomal dominant polycystic kidney diseaseGlis2Primary ciliaKidney tubule cellsSignaling pathwayMouse modelDominant polycystic kidney diseasePotential therapeutic targetTranslatomeAntisense oligonucleotidesKidney diseasePolycystinMouse kidneyFunctional effectorsCyst formationTherapeutic targetInactivationFunctional targetPharmacological targets
2023
Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis
Tenney A, Di Gioia S, Webb B, Chan W, de Boer E, Garnai S, Barry B, Ray T, Kosicki M, Robson C, Zhang Z, Collins T, Gelber A, Pratt B, Fujiwara Y, Varshney A, Lek M, Warburton P, Van Ryzin C, Lehky T, Zalewski C, King K, Brewer C, Thurm A, Snow J, Facio F, Narisu N, Bonnycastle L, Swift A, Chines P, Bell J, Mohan S, Whitman M, Staffieri S, Elder J, Demer J, Torres A, Rachid E, Al-Haddad C, Boustany R, Mackey D, Brady A, Fenollar-Cortés M, Fradin M, Kleefstra T, Padberg G, Raskin S, Sato M, Orkin S, Parker S, Hadlock T, Vissers L, van Bokhoven H, Jabs E, Collins F, Pennacchio L, Manoli I, Engle E. Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis. Nature Genetics 2023, 55: 1149-1163. PMID: 37386251, PMCID: PMC10335940, DOI: 10.1038/s41588-023-01424-9.Peer-Reviewed Original ResearchConceptsSingle-nucleotide variantsGATA2 expressionHereditary congenital facial paresisBranchial motor neuronsLoss of GATA3Temporal gene regulationRare Mendelian diseasesChromosome 3q21-q22Autosomal dominant disorderSilencing in vitroNoncoding variationNoncoding variantsFacial paresisMendelian diseasesGene regulationRegulatory regionsHeterozygous duplicationDominant disorderMouse modelReporter expressionType 1Efferent neuronsMotor neuronsGATA2In vivo
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