Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene

Ishibashi, Minaka, Manning, Elizabeth, Shoubridge, Cheryl, Krecsmarik, Monika, Hawkins, Thomas A, Giacomotto, Jean, Zhao, Ting, Mueller, Thomas, Bader, Patricia I., Cheung, Sau W., Stankiewicz, Pawel, Bain, Nicole L., Hackett, Anna, Reddy, Chilamakuri C. S., Mechaly, Alejandro S., Peers, Bernard, Wilson, Stephen W., Lenhard, Boris, Bally-Cuif, Laure, Gecz, Jozef, Becker, Thomas S. and Rinkwitz, Silke (2015) Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene. Human Genetics, 134 11-12: 1163-1182. doi:10.1007/s00439-015-1594-x


Author Ishibashi, Minaka
Manning, Elizabeth
Shoubridge, Cheryl
Krecsmarik, Monika
Hawkins, Thomas A
Giacomotto, Jean
Zhao, Ting
Mueller, Thomas
Bader, Patricia I.
Cheung, Sau W.
Stankiewicz, Pawel
Bain, Nicole L.
Hackett, Anna
Reddy, Chilamakuri C. S.
Mechaly, Alejandro S.
Peers, Bernard
Wilson, Stephen W.
Lenhard, Boris
Bally-Cuif, Laure
Gecz, Jozef
Becker, Thomas S.
Rinkwitz, Silke
Title Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene
Formatted title
Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene
Journal name Human Genetics   Check publisher's open access policy
ISSN 1432-1203
0340-6717
Publication date 2015-11-01
Year available 2015
Sub-type Article (original research)
DOI 10.1007/s00439-015-1594-x
Open Access Status Not Open Access
Volume 134
Issue 11-12
Start page 1163
End page 1182
Total pages 20
Place of publication Heidelberg, Germany
Publisher Springer
Language eng
Formatted abstract
Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.
Keyword Genetics & Heredity
Genetics & Heredity
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 223262
1008077
FT120100086
1041920
BB/H012516/1
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Queensland Brain Institute Publications
 
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Created: Sun, 31 Jan 2016, 20:21:16 EST by Jean Giacomotto on behalf of Learning and Research Services (UQ Library)