A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability

Kumar, Raman, Ha, Thuong, Pham, Duyen, Shaw, Marie, Mangelsdorf, Marie, Friend, Kathryn L, Hobson, Lynne, Turner, Gillian, Boyle, Jackie, Field, Michael, Hackett, Anna, Corbett, Mark and Gecz, Jozef (2016) A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability. European Journal of Human Genetics, 24 11: 1612-1616. doi:10.1038/ejhg.2016.46


Author Kumar, Raman
Ha, Thuong
Pham, Duyen
Shaw, Marie
Mangelsdorf, Marie
Friend, Kathryn L
Hobson, Lynne
Turner, Gillian
Boyle, Jackie
Field, Michael
Hackett, Anna
Corbett, Mark
Gecz, Jozef
Title A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability
Formatted title
A non-coding variant in the 5' UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability
Journal name European Journal of Human Genetics   Check publisher's open access policy
ISSN 1018-4813
1476-5438
Publication date 2016-05-26
Year available 2016
Sub-type Article (original research)
DOI 10.1038/ejhg.2016.46
Open Access Status Not yet assessed
Volume 24
Issue 11
Start page 1612
End page 1616
Total pages 5
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
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.
Formatted 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 5สน 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.
Keyword Biochemistry & Molecular Biology
Genetics & Heredity
Biochemistry & Molecular Biology
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1008077
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
 
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Created: Tue, 27 Sep 2016, 21:19:24 EST by Kirstie Asmussen on behalf of School of Music