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Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.
Tenney, Alan P; Di Gioia, Silvio Alessandro; Webb, Bryn D; Chan, Wai-Man; de Boer, Elke; Garnai, Sarah J; Barry, Brenda J; Ray, Tammy; Kosicki, Michael; Robson, Caroline D; Zhang, Zhongyang; Collins, Thomas E; Gelber, Alon; Pratt, Brandon M; Fujiwara, Yuko; Varshney, Arushi; Lek, Monkol; Warburton, Peter E; Van Ryzin, Carol; Lehky, Tanya J; Zalewski, Christopher; King, Kelly A; Brewer, Carmen C; Thurm, Audrey; Snow, Joseph; Facio, Flavia M; Narisu, Narisu; Bonnycastle, Lori L; Swift, Amy; Chines, Peter S; Bell, Jessica L; Mohan, Suresh; Whitman, Mary C; Staffieri, Sandra E; Elder, James E; Demer, Joseph L; Torres, Alcy; Rachid, Elza; Al-Haddad, Christiane; Boustany, Rose-Mary; Mackey, David A; Brady, Angela F; Fenollar-Cortés, María; Fradin, Melanie; Kleefstra, Tjitske; Padberg, George W; Raskin, Salmo; Sato, Mario Teruo; Orkin, Stuart H; Parker, Stephen C J.
Afiliação
  • Tenney AP; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Di Gioia SA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Webb BD; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Chan WM; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • de Boer E; Regeneron Pharmaceuticals, Tarrytown, NY, USA.
  • Garnai SJ; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
  • Barry BJ; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Ray T; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kosicki M; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Robson CD; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Zhang Z; Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Collins TE; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Gelber A; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Pratt BM; Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA.
  • Fujiwara Y; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Varshney A; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Lek M; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • Warburton PE; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Van Ryzin C; Environmental Genomics & System Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
  • Lehky TJ; Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Zalewski C; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • King KA; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Brewer CC; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Thurm A; Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Snow J; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
  • Facio FM; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • Narisu N; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • Bonnycastle LL; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Swift A; Center for Advanced Genomics Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Chines PS; Metabolic Medicine Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Bell JL; EMG Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
  • Mohan S; Audiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
  • Whitman MC; Audiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
  • Staffieri SE; Audiology Unit, Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD, USA.
  • Elder JE; Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, NIH, Bethesda, MD, USA.
  • Demer JL; Office of the Clinical Director, National Institute of Mental Health, NIH, Bethesda, MD, USA.
  • Torres A; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Rachid E; Invitae Corporation, San Francisco, CA, USA.
  • Al-Haddad C; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Boustany RM; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Mackey DA; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Brady AF; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD, USA.
  • Fenollar-Cortés M; Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Fradin M; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
  • Kleefstra T; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
  • Padberg GW; Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Raskin S; Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, and University of Melbourne, Melbourne, Victoria, Australia.
  • Sato MT; Department of Ophthalmology, Royal Children's Hospital, Parkville, Victoria, Australia.
  • Orkin SH; Department of Ophthalmology, Royal Children's Hospital, Parkville, Victoria, Australia.
  • Parker SCJ; Stein Eye Institute and Departments of Ophthalmology, Neurology, and Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.
Nat Genet ; 55(7): 1149-1163, 2023 07.
Article em En | MEDLINE | ID: mdl-37386251
ABSTRACT
Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Paralisia Facial Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
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PubMed Links
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Paralisia Facial Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos