@article{e1d42cde645643b9bcf75614277b4e1f,
title = "Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis",
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.",
author = "Tenney, \{Alan P.\} and \{Di Gioia\}, \{Silvio Alessandro\} and Webb, \{Bryn D.\} and Chan, \{Wai Man\} and \{de Boer\}, Elke and Garnai, \{Sarah J.\} and Barry, \{Brenda J.\} and Tammy Ray and Michael Kosicki and Robson, \{Caroline D.\} and Zhongyang Zhang and Collins, \{Thomas E.\} and Alon Gelber and Pratt, \{Brandon M.\} and Yuko Fujiwara and Arushi Varshney and Monkol Lek and Warburton, \{Peter E.\} and \{Van Ryzin\}, Carol and Lehky, \{Tanya J.\} and Christopher Zalewski and King, \{Kelly A.\} and Brewer, \{Carmen C.\} and Audrey Thurm and Joseph Snow and Facio, \{Flavia M.\} and Narisu Narisu and Bonnycastle, \{Lori L.\} and Amy Swift and Chines, \{Peter S.\} and Bell, \{Jessica L.\} and Suresh Mohan and Whitman, \{Mary C.\} and Staffieri, \{Sandra E.\} and Elder, \{James E.\} and Demer, \{Joseph L.\} and Alcy Torres and Elza Rachid and Christiane Al-Haddad and Boustany, \{Rose Mary\} and Mackey, \{David A.\} and Brady, \{Angela F.\} and Mar{\'i}a Fenollar-Cort{\'e}s and Melanie Fradin and Tjitske Kleefstra and Padberg, \{George W.\} and Salmo Raskin and Sato, \{Mario Teruo\} and Orkin, \{Stuart H.\} and Parker, \{Stephen C.J.\} and Hadlock, \{Tessa A.\} and Vissers, \{Lisenka E.L.M.\} and \{van Bokhoven\}, Hans and Jabs, \{Ethylin Wang\} and Collins, \{Francis S.\} and Pennacchio, \{Len A.\} and Irini Manoli and Engle, \{Elizabeth C.\}",
note = "Funding Information: We thank the following: all members of the U01HD079068 Consortium; V. McCarrell and the Moebius Syndrome Foundation, C. Andrews, K. Hao, K. Ismail, J. Lee, B. B. Biesecker, A. Zingaro, S. Dogar, L. Goodrich, B. Fritzsch and members of the Engle laboratory for their contributions and insightful discussions; the Regev laboratory and Broad Institute Klarman Cell Observatory; and the BioTuring User Support Team: E. van Beusekom, M. Kwint, Ro. van Beek, T. Mantere, K. Neveling, E. van der Looij, M. Schouten, J. van Reeuwijk, A. den Ouden, R. Derks, J. C. Galbany, C. Gilissen, the Radboudumc Technology Center Genomics and the Radboudumc Cell Culture Facility for their clinical, technical and bioinformatic support. The Gata3 and Gata3 mice were kindly shared by F. Grosveld (Erasmus Medical Center, the Netherlands) and J. Zhu (NIH–National Institute of Allergy and Infectious Diseases), respectively, and provided to us by L. Goodrich (Harvard Medical School). The anti-ISL1 antibody was a generous gift from S. Morton and T. Jessell (Columbia University). We also acknowledge the use of: Boston Children{\textquoteright}s Hospital F.M. Kirby Neurobiology Center and IDDRC Gene Editing, Neurodevelopmental Behavioral, Molecular Genetics and Administrative Cores; Boston Children{\textquoteright}s Hospital Hematology/Oncology Flow Cytometry Research Facility; the Broad Institute Genomics Platform; Harvard Medical School OGI Core; the NIH Intramural Sequencing Center; the NHGRI Genomic Core; and the Gene Targeting and Transgenic Facility at Albert Einstein College of Medicine. The work was supported by: an NIH Gabriella Miller Kids First Pediatric Research Program (grant no. X01 HL132377 to E.C.E.); NIH (grant no. U01HD079068 to E.W.J., I.M. and E.C.E.); William Randolph Hearst Fund Grant (to S.A.D.G.); Moebius Syndrome Foundation grants (to A.P.T., B.D.W., Z.Z. and F.M.F.); Boston Children{\textquoteright}s Hospital—Broad Institute Collaborative Grant (to E.C.E.); NIH (grant no. R01HG003988 to L.A.P.); NIH Intramural Research Programs of the National Institute on Deafness and Other Communication Disorders (to C.Z., K.A.K. and C.C.B.), National Institute of Neurological Disorders and Stroke (T.J.L.), National Institute of Mental Health (J.S.); NIH Intramural projects (no. 1ZICMH002961 to A.T.) and NIH ZIA (grant no. HG200389 to F.S.C., N.N., L.B. and A.S.); Boston Children{\textquoteright}s Hospital Intellectual and Developmental Disabilities Research Center (grant no. 1U54HD090255); Solve-RD project (to E.d.B., T.K. and L.V.) which received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 779257; HMS George Cheyne Shattuck Memorial Fund (to S.J.G.); American University of Beirut OpenMinds Fund (to R.-M.B.); and National Health and Medical Research Council CRE Translation of Genetic Eye research grant (no. GNT1116360 to S.E.S. and A.M.). This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and Clinical and Translational Science Awards (grant no. UL1TR004419) from the National Center for Advancing Translational Sciences, NIH. The research of L.A.P. and M.K. was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under the US Department of Energy contract (no. DE-AC02-05CH11231), University of California. The Centre for Eye Research Australia (S.E.S.) receives operational infrastructure support from the government in Victoria. E.C.E. and S.H.O. are Howard Hughes Medical Institute investigators. tlz flox Funding Information: We thank the following: all members of the U01HD079068 Consortium; V. McCarrell and the Moebius Syndrome Foundation, C. Andrews, K. Hao, K. Ismail, J. Lee, B. B. Biesecker, A. Zingaro, S. Dogar, L. Goodrich, B. Fritzsch and members of the Engle laboratory for their contributions and insightful discussions; the Regev laboratory and Broad Institute Klarman Cell Observatory; and the BioTuring User Support Team: E. van Beusekom, M. Kwint, Ro. van Beek, T. Mantere, K. Neveling, E. van der Looij, M. Schouten, J. van Reeuwijk, A. den Ouden, R. Derks, J. C. Galbany, C. Gilissen, the Radboudumc Technology Center Genomics and the Radboudumc Cell Culture Facility for their clinical, technical and bioinformatic support. The Gata3tlzand Gata3floxmice were kindly shared by F. Grosveld (Erasmus Medical Center, the Netherlands) and J. Zhu (NIH–National Institute of Allergy and Infectious Diseases), respectively, and provided to us by L. Goodrich (Harvard Medical School). The anti-ISL1 antibody was a generous gift from S. Morton and T. Jessell (Columbia University). We also acknowledge the use of: Boston Children{\textquoteright}s Hospital F.M. Kirby Neurobiology Center and IDDRC Gene Editing, Neurodevelopmental Behavioral, Molecular Genetics and Administrative Cores; Boston Children{\textquoteright}s Hospital Hematology/Oncology Flow Cytometry Research Facility; the Broad Institute Genomics Platform; Harvard Medical School OGI Core; the NIH Intramural Sequencing Center; the NHGRI Genomic Core; and the Gene Targeting and Transgenic Facility at Albert Einstein College of Medicine. The work was supported by: an NIH Gabriella Miller Kids First Pediatric Research Program (grant no. X01 HL132377 to E.C.E.); NIH (grant no. U01HD079068 to E.W.J., I.M. and E.C.E.); William Randolph Hearst Fund Grant (to S.A.D.G.); Moebius Syndrome Foundation grants (to A.P.T., B.D.W., Z.Z. and F.M.F.); Boston Children{\textquoteright}s Hospital—Broad Institute Collaborative Grant (to E.C.E.); NIH (grant no. R01HG003988 to L.A.P.); NIH Intramural Research Programs of the National Institute on Deafness and Other Communication Disorders (to C.Z., K.A.K. and C.C.B.), National Institute of Neurological Disorders and Stroke (T.J.L.), National Institute of Mental Health (J.S.); NIH Intramural projects (no. 1ZICMH002961 to A.T.) and NIH ZIA (grant no. HG200389 to F.S.C., N.N., L.B. and A.S.); Boston Children{\textquoteright}s Hospital Intellectual and Developmental Disabilities Research Center (grant no. 1U54HD090255); Solve-RD project (to E.d.B., T.K. and L.V.) which received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under grant agreement no. 779257; HMS George Cheyne Shattuck Memorial Fund (to S.J.G.); American University of Beirut OpenMinds Fund (to R.-M.B.); and National Health and Medical Research Council CRE Translation of Genetic Eye research grant (no. GNT1116360 to S.E.S. and A.M.). This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and Clinical and Translational Science Awards (grant no. UL1TR004419) from the National Center for Advancing Translational Sciences, NIH. The research of L.A.P. and M.K. was conducted at the E.O. Lawrence Berkeley National Laboratory and performed under the US Department of Energy contract (no. DE-AC02-05CH11231), University of California. The Centre for Eye Research Australia (S.E.S.) receives operational infrastructure support from the government in Victoria. E.C.E. and S.H.O. are Howard Hughes Medical Institute investigators. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = jul,
doi = "10.1038/s41588-023-01424-9",
language = "English",
volume = "55",
pages = "1149--1163",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "7",
}