title: Mutations affecting the SAND domain of DEAF1 cause intellectual disability with severe speech impairment and behavioral problems.
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.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Rajamanickam
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Jensik
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vergult
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
authors.forename: Nina
authors.initials: N
authors.lastname: de Rocker
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Newhall
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Ramya
authors.initials: R
authors.lastname: Raghavan
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Reardon
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Jarrett
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: McIntyre
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bulinski
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Ownby
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Jodi I
authors.initials: JI
authors.lastname: Huggenvik
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.
authors.forename: G Stanley
authors.initials: GS
authors.lastname: McKnight
authors.affiliation: Department 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.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rose
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
authors.forename: Andy
authors.initials: A
authors.lastname: Willaert
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Zweier
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Endele
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Bregje W M
authors.initials: BW
authors.lastname: van Bon
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Petra F
authors.initials: PF
authors.lastname: de Vries
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department 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.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Institute 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.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Department 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.
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Carvill
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Lisenka E L M
authors.initials: LE
authors.lastname: Vissers
authors.affiliation: Center for Medical Genetics, Ghent University, Ghent 9000, Belgium.
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
authors.affiliation: Department of Physiology and Center for Integrated Research in Cognitive & Neural Sciences, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Collard
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: bert.devries@radboudumc.nl.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D013064:Speech Disorders / Q000235:genetics*; D014157:Transcription Factors
chemical_list: C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; C548809:Deaf1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors
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