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. 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

Teesta Naskar  1 , Mohammed Faruq  2 , Priyajit Banerjee  3 , Massarat Khan  4 , Rashi Midha  5 , Renu Kumari  6 , Subhashree Devasenapathy  5 , Bharat Prajapati  5 , Sanghamitra Sengupta  7 , Deepti Jain  3 , Mitali Mukerji  2 , Nandini Chatterjee Singh  5 , Subrata Sinha  8
Affiliations

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

Teesta Naskar et al. EBioMedicine. 2018 Feb.

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.

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Figures

Fig. 1
Fig. 1
Variations co-segregating with familial dyslexia following dominant inheritance pattern. Pedigree of the extended family KA25. Black filled symbols indicate individuals with dyslexia; white symbols indicate asymptomatic individuals. Symbols with question marks indicate undiagnosed/unknown dyslexia status, ‘n’ within diamond shaped box indicates unknown lineage information and NA marked individuals have been excluded from the study due to unavailability. Generations are marked with Roman numbers on the left of the image and individuals are counted from left to right. Names of the 17 variations are written on the extreme left of the image and the genotypes of these variants are written under each members of family. Genotypes enclosed in the box indicate the risk haplotype. Individuals marked with asterisk were selected for exome sequencing while the SNP array was performed for entire family.
Fig. 2
Fig. 2
Overview of variations in chr5q31.3. Schematic diagram includes PCDHG gene cluster of chromosome 5q31.3 from approximately 140,690,000–140,890,000 bp, drawn to scale (with coordinates according to GRCh37/hg19 taken from UCSC genome browser). First exons of each isoform genes are depicted as filled blue box. SNPs indicated with red colored lines.
Fig. 3
Fig. 3
Incidence of lineage specific variations of PCDHG gene cluster. Figure depicts the multiple sequence alignments of seven variations throughout primates to Neanderthal to human lineage. The identified variations where the risk allele is the ancestral while the non-risk allele is the preponderant human form, are marked with arrow. The respective alleles are bordered with a red-brown box.
Fig. 4
Fig. 4
Alterations of γA4-PCDH and γA3-PCDH are present in the interacting interface of specificity determining region. (a) Schematic diagram of γA4-PCDH and (b) γA3-PCDH depicting the position of the amino acid alteration. Extracellular domain (EC), transmembrane domain (TM) and cytoplasmic domain (CP) are labeled. (c) The portion of the sequence alignment among different orthologs of γA3PCDH and (d) γA4PCDH showing interfacing region of EC2: EC3. (e) Homology model of the trans dimer of the wild type γA3PCDH (EC1–3) and (f) wild type γA4PCDH (EC1–3). The structures are depicted in ribbon and bound calcium ions are seen as cyan spheres. The residues Leu154 in γA3PCDH and Ala181 in γA4PCDH are shown in red stick. The inset shows enlarged view of the wild type proteins at the top and mutants in the lower panel. The amino acids are shown as sticks and hydrogen bond is shown as a black broken line. (g) Electrostatic surface potential of wild type and altered γA3PCDH and (h) wild type and altered γA4PCDH wild type and altered colored according to the bar underneath. The trans homophilic interaction interface is highlighted using green (EC2) and yellow (EC3) outline. Sites of alterations are marked with arrow in both cases. (i) Alignment of the interfacing region in the homology models among human γPCDH isoforms showing sequence variability within the interaction interface of EC2 and EC3.
Fig. 5
Fig. 5
Species specific isoform identity of p.Arg679Pro and p.Lys687Glu. (a) Schematic diagram of γB2PCDH depicting the position of the amino acid alteration. Extracellular domain (EC), transmembrane domain (TM) and cytoplasmic domain (CD) are labeled. (b) Multiple sequence alignment among the loop region of γB2PCDH primate orthologs showing human specific variations by arrows. (c) Multiple sequence alignment of loop region connecting EC6 and TM domain of human γB2PCDH among different isoforms. Altered residues are shown with arrow.
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Web resources

    1. 1000 genome http://www.1000genomes.org
    1. dbSNP http://www.ncbi.nlm.nih.gov/projects/SNP
    1. UCSC Genome Browser https://genome.ucsc.edu
    1. Ancient Genome Browser https://bioinf.eva.mpg.de/jbrowse
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