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Naskar, Teesta and Mohammed, Faruq and Banerjee, Priyajit and Khan, Massarat and Midha, Rashi and Kumari, Renu and Devasenapathy, Subhashree and Prajapati, Bharat and Sengupta, Sanghamitra and Jain, Deepti and Mukerji, Mitali and Singh, Nandini Chatterjee and Sinha, Subrata (2018) Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family. EBioMedicine, 28. pp. 168-179.

Ancestral Variations of the PCDHG Gene Cluster Predispose to Dyslexia in a Multiplex Family.pdf

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Dyslexia is a heritable neurodevelopmental disorder characterized by difficulties in reading and writing. In this study, we describe the identification of a set of 17 polymorphisms located across 1.9 Mb region on chromosome 5q31.3, encompassing genes of the PCDHG cluster, TAF7, PCDH1 and ARHGAP26, dominantly inherited with dyslexia in a multi-incident family. Strikingly, the non-risk form of seven variations of the PCDHG cluster, are preponderant in the human lineage, while risk alleles are ancestral and conserved across Neanderthals to non-human primates. Four of these seven ancestral variations (c.460A > C [p.Ile154Leu], c.541G > A [p.Ala181Thr], c.2036G > C [p.Arg679Pro] and c.2059A > G [p.Lys687Glu]) result in amino acid alterations. p.Ile154Leu and p.Ala181Thr are present at EC2: EC3 interacting interface of γA3-PCDH and γA4-PCDH respectively might affect trans-homophilic interaction and hence neuronal connectivity. p.Arg679Pro and p.Lys687Glu are present within the linker region connecting trans-membrane to extracellular domain. Sequence analysis indicated the importance of p.Ile154, p.Arg679 and p.Lys687 in maintaining class specificity. Thus the observed association of PCDHG genes encoding neural adhesion proteins reinforces the hypothesis of aberrant neuronal connectivity in the pathophysiology of dyslexia. Additionally, the striking conservation of the identified variants indicates a role of PCDHG in the evolution of highly specialized cognitive skills critical to reading

Item Type: Article
Subjects: Neurodegenerative Disorders
Neuro-Oncological Disorders
Neurocognitive Processes
Neuronal Development and Regeneration
Informatics and Imaging
Genetics and Molecular Biology
Depositing User: Dr. D.D. Lal
Date Deposited: 09 May 2018 09:33
Last Modified: 24 Feb 2022 04:05
URI: http://nbrc.sciencecentral.in/id/eprint/347

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