Send to

Choose Destination
Hum Genet. 2015 Nov;134(11-12):1163-82. doi: 10.1007/s00439-015-1594-x. Epub 2015 Sep 4.

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

Author information

Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.
School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA, 5006, Australia.
Laboratory of Neurobiology and Development, CNRS, Institute of Neurobiology Alfred Fessard, 91198, Gif-sur-Yvette Cédex, France.
Department of Cell and Developmental Biology, UCL, London, WC1E 6BT, UK.
Department of Neurology, The People's hospital of Zhengzhou University, Henan, 450003, China.
Division of Biology, Kansas State University, Manhattan, KS, 66502, USA.
Parkview Cytogenetics and Northeast Indiana Genetics, Fort Wayne, IN, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, USA.
Department of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
Genetics of Learning Disability Service, Hunter Genetics, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, 2305, Australia.
Department of Biology and Bergen Center for Computational Science, University of Bergen, 5008, Bergen, Norway.
Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Laboratorio de Ictiofisiología y Acuicultura, Instituto Tecnológico de Chascomús (IIB-INTECH) (CONICET-UNSAM), Buenos Aires, Argentina.
GIGA Research, Universite de Liege, 4000, Liege, Belgium.
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, UK.
MRC Clinical Sciences Centre, London, UK.
Neurogenetics Laboratory, Genetics and Molecular Pathology, SA Pathology at the Women's and Children's Hospital, Adelaide, SA, 5006, Australia.
Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.


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.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center