title: A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability.
abstract: Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may be associated with additional dysmorphic, metabolic, neuromuscular or psychiatric features. Although many coding variants have been implicated in ID, identification of pathogenic non-coding regulatory variants has only been achieved in a few cases to date. We identified a duplication of a guanine on chromosome X, NC_000023.10:g.69665044dupG 7 nucleotides upstream of the translational start site in the 5' untranslated region (UTR) of the known ID gene DLG3 that encodes synapse-associated protein 102 (SAP102). The dupG variant segregated with affected status in a large multigenerational family with non-syndromic X-linked ID and was predicted to disrupt folding of the mRNA. When tested on blood cells from the affected individuals, DLG3 mRNA levels were not altered, however, DLG3/SAP102 protein levels were. We also showed by dual luciferase reporter assay that the dupG variant interfered with translation. All currently known pathogenic DLG3 variants are predicted to be null, however the dupG variant likely leads to only a modest reduction of SAP102 levels accounting for the milder phenotype seen in this family.
authors.affiliation: School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Raman
authors.initials: R
authors.lastname: Kumar
authors.affiliation: School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Thuong
authors.initials: T
authors.lastname: Ha
authors.affiliation: School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Duyen
authors.initials: D
authors.lastname: Pham
authors.affiliation: School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Marie
authors.initials: M
authors.lastname: Mangelsdorf
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Friend
authors.affiliation: Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Hobson
authors.affiliation: The GOLD service Hunter Genetics, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Gillian
authors.initials: G
authors.lastname: Turner
authors.affiliation: The GOLD service Hunter Genetics, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Jackie
authors.initials: J
authors.lastname: Boyle
authors.affiliation: The GOLD service Hunter Genetics, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Field
authors.affiliation: The GOLD service Hunter Genetics, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Hackett
authors.affiliation: School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Corbett
authors.affiliation: School of Medicine and the Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia.|School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D059370:RNA Folding; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C116869:DLG3 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors