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

Human Genetics
Minaka IshibashiSilke Rinkwitz

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...Continue Reading

References

Jul 1, 1995·Developmental Dynamics : an Official Publication of the American Association of Anatomists·C B KimmelT F Schilling
Aug 1, 1996·Anatomy and Embryology·B RuppH Reichert
Jul 13, 2000·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·P BermanW Miller
Oct 17, 2003·Genes & Development·Patrick CollombatPeter Gruss
Dec 19, 2003·Nucleic Acids Research·Albin SandelinBoris Lenhard
Feb 26, 2004·The Journal of Comparative Neurology·Mario F Wullimann, Thomas Mueller
May 26, 2004·Brain Research·Elke Rink, Mario F Wullimann
Jun 25, 2004·Nucleic Acids Research·Albin SandelinBoris Lenhard
Sep 18, 2004·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Elena ColomboVania Broccoli
Dec 23, 2004·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Daniel W SeufertHeithem M El-Hodiri
Mar 8, 2006·The European Journal of Neuroscience·Gaëlle FriocourtJamel Chelly
May 3, 2006·Current Opinion in Genetics & Development·Jozef GéczMichael Partington
Sep 22, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jiho SohnVittorio Gallo
Dec 6, 2006·Proceedings of the National Academy of Sciences of the United States of America·William R Jackman, David W Stock
Sep 14, 2007·Molecular Genetics and Genomics : MGG·Thomas S Becker, Boris Lenhard
Oct 13, 2007·Cell Death and Differentiation·S BiressiG Cossu
May 30, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gaëlle FriocourtJohn G Parnavelas
Jul 16, 2008·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Beena PunnamoottilSilke Rinkwitz
Sep 6, 2008·Science·Joung-Woo HongMichael S Levine
Sep 19, 2008·Human Molecular Genetics·Carl T FulpJeffrey A Golden
Oct 17, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Gaia ColasanteVania Broccoli
Feb 13, 2009·Nature·Axel ViselLen A Pennacchio
Jul 17, 2009·Briefings in Functional Genomics & Proteomics·David FredmanBoris Lenhard
Jul 25, 2009·Proceedings of the National Academy of Sciences of the United States of America·Martin DistelReinhard W Köster
Sep 29, 2009·Developmental Biology·Anna Z KomisarczukThomas S Becker
Jan 9, 2010·The Journal of Comparative Neurology·Joana OsórioMario F Wullimann
May 28, 2010·Human Mutation·Cheryl ShoubridgeJozef Gécz
Jul 27, 2010·American Journal of Human Genetics·Annabel C WhibleyF Lucy Raymond

❮ Previous
Next ❯

Citations

Jun 2, 2017·Birth Defects Research·Huilin WangKwong Wai Choy
Aug 17, 2019·Frontiers in Cellular Neuroscience·Elena PerenthalerTahsin Stefan Barakat
Dec 5, 2017·Comparative Biochemistry and Physiology. Toxicology & Pharmacology : CBP·Adrian J Green, Antonio Planchart
Mar 25, 2021·BMC Research Notes·Yousra BenmakhloufMohcine Bennani Mechita

❮ Previous
Next ❯

Related Concepts

Related Feeds

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Autism: Treatment Targets

The absence of effective treatments for autism are due to the high clinical and genetic heterogeneity between affected individuals, restricted knowledge of the underlying pathophysiological mechanisms, and the lack of reliable diagnostic biomarkers. Identification of more homogenous biological subgroups is therefore essential for the development of novel treatments based on the molecular mechanisms underpinning autism and autism spectrum disorders. Find the latest research on autism treatment targets here.

Autism

Autism spectrum disorder is associated with challenges with social skills, repetitive behaviors, and often accompanied by sensory sensitivities and medical issues. Here is the latest research on autism.