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EBioMedicine. 2018 Feb;28:168-179. doi: 10.1016/j.ebiom.2017.12.031. Epub 2018 Jan 9.

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

Author information

1
Cellular and Molecular Neuroscience Division, National Brain Research Centre, Manesar, Gurgaon, Haryana 122051, India; Department of Biochemistry, University of Calcutta, Kolkata, West Bengal 700019, India.
2
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India.
3
Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana 121001, India.
4
Maharashtra Dyslexia Association, Mumbai, Maharashtra 400088, India.
5
Cellular and Molecular Neuroscience Division, National Brain Research Centre, Manesar, Gurgaon, Haryana 122051, India.
6
Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi 110007, India; Academy of Scientific and Innovative Research, CSIR-Institute of Genomics & Integrative Biology (AcSIR-IGIB), New Delhi 110020, India.
7
Department of Biochemistry, University of Calcutta, Kolkata, West Bengal 700019, India.
8
Cellular and Molecular Neuroscience Division, National Brain Research Centre, Manesar, Gurgaon, Haryana 122051, India; Department of Biochemistry, All India Institute of Medical Sciences, New Delhi 110029, India. Electronic address: subrata.sinha@nbrc.ac.in.

Abstract

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 1.9Mb 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.

KEYWORDS:

Ancestral variations; Dominant inheritance; Dyslexia; Neanderthal genome; Neuronal connection; Protocadherin gamma; Trans-homophilic interaction

PMID:
29409727
PMCID:
PMC5835549
DOI:
10.1016/j.ebiom.2017.12.031
[Indexed for MEDLINE]
Free PMC Article

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