ArticleAmerican journal of human genetics2014
Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.
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Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed, 67 citations in OpenAlex.
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Authors and funding
36 authors at 7 institutions in 5 countries.
Anneke T Vulto-van SilfhoutDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Shivakumar RajamanickamDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Philip J JensikDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Sarah VergultCenter for Medical Genetics, Ghent University, Ghent 9000, Belgium.
Nina de RockerCenter for Medical Genetics, Ghent University, Ghent 9000, Belgium.
Kathryn J NewhallDepartment of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Ramya RaghavanDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Sara N ReardonDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Kelsey JarrettDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Tara McIntyreDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Joseph BulinskiDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Stacy L OwnbyDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Jodi I HuggenvikDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
G Stanley McKnightDepartment of Pharmacology, University of Washington, Seattle, WA 98195, USA.
Gregory M RoseDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Xiang CaiDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Andy WillaertCenter for Medical Genetics, Ghent University, Ghent 9000, Belgium.
Christiane ZweierInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Sabine EndeleInstitute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
Joep de LigtDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Bregje W M van BonDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Dorien LugtenbergDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Petra F de VriesDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Joris A VeltmanDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Hans van BokhovenDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Cognitive Neurosciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Han G BrunnerDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Anita RauchInstitute of Medical Genetics, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland; Neuroscience Center Zurich, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland; Zurich Center of Integrative Human Physiology, University of Zurich, 8603 Schwerzenbach-Zurich, Switzerland.
Arjan P M de BrouwerDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Cognitive Neurosciences, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Gemma L CarvillDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Alexander HoischenDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Heather C MeffordDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Evan E EichlerDepartment of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Lisenka E L M VissersDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
Björn MentenCenter for Medical Genetics, Ghent University, Ghent 9000, Belgium.
Michael W CollardDepartment of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
Bert B A de VriesDepartment of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: bert.devries@radboudumc.nl.
Southern Illinois University School of Medicine · USRadboud University Medical Center · NLRadboud University Nijmegen · NLUniversity of Washington · USGhent University Hospital · BEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEUniversity of Zurich · CH
Funding
REGULATION OF CYCLIC AMP-DEPENDENT PROTEIN KINASE GENESR01GM032875 · NIGMS · UNIVERSITY OF WASHINGTON · PI MCKNIGHT, GEORGE STANLEY · 1985 to 2017
$6.0MNUDR--A Potential Tumor Suppressor of Childhood CancersR01CA089438 · NCI · SOUTHERN ILLINOIS UNIVERSITY CARBONDALE · PI HUGGENVIK, JODI · 2001 to 2005
$1.4MDEAF-1 Interactions and Protein Modifications in Prostate CellsR15CA137556 · NCI · SOUTHERN ILLINOIS UNIVERSITY CARBONDALE · PI HUGGENVIK, JODI · 2009 to 2009
$218kRegulatory Mechanisms of DEAF-1 in DevelopmentR15HD060122 · NICHD · SOUTHERN ILLINOIS UNIVERSITY CARBONDALE · PI COLLARD, MICHAEL W · 2009 to 2009
$218kNCI NIH HHS CA137556NCI NIH HHS CA89438NCI NIH HHS R01 CA089438NCI NIH HHS R15 CA137556NICHD NIH HHS HD060122NICHD NIH HHS R15 HD060122NIGMS NIH HHS R01 GM032875
Abstract
Recently, we identified in two individuals with intellectual disability (ID) different de novo mutations in DEAF1, which encodes a transcription factor with an important role in embryonic development. To ascertain whether these mutations in DEAF1 are causative for the ID phenotype, we performed targeted resequencing of DEAF1 in an additional cohort of over 2,300 individuals with unexplained ID and identified two additional individuals with de novo mutations in this gene. All four individuals had severe ID with severely affected speech development, and three showed severe behavioral problems. DEAF1 is highly expressed in the CNS, especially during early embryonic development. All four mutations were missense mutations affecting the SAND domain of DEAF1. Altered DEAF1 harboring any of the four amino acid changes showed impaired transcriptional regulation of the DEAF1 promoter. Moreover, behavioral studies in mice with a conditional knockout of Deaf1 in the brain showed memory deficits and increased anxiety-like behavior. Our results demonstrate that mutations in DEAF1 cause ID and behavioral problems, most likely as a result of impaired transcriptional regulation by DEAF1.
Indexed as
Amino Acid SequenceAnimalsChildCohort StudiesDNA-Binding ProteinsDNA Mutational AnalysisFemaleHumansIntellectual DisabilityMaleMental DisordersMiceMice, KnockoutMolecular Sequence DataMutationNuclear ProteinsDEAF1 protein, humanDeaf1 protein, mouseDNA-Binding ProteinsNuclear ProteinsTranscription Factors
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