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. 2013 Jul 11;93(1):19-28.
doi: 10.1016/j.ajhg.2013.05.008. Epub 2013 Jun 6.

Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment

Natalie R Powers  1 , John D Eicher, Falk Butter, Yong Kong, Laura L Miller, Susan M Ring, Matthias Mann, Jeffrey R Gruen
Affiliations

Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment

Natalie R Powers et al. Am J Hum Genet. .

Erratum in

  • Am J Hum Genet. 2014 May 1;94(5):798

Abstract

Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1."

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Figures

Figure 1
Figure 1
READ1 Is a Highly Polymorphic STR Located Near the DCDC2 Risk Haplotype Block (A) Structure of the READ1 STR. (B) Location of the DCDC2 risk-haplotype block (blue line) relative to the microdeletion (yellow box) and the READ1 STR (purple line) it encompasses. Exons are numbered. (C) Alignment of READ1 and flanking sequence from human, chimpanzee, and gorilla DCDC2. READ1 is highlighted for all three species. Note the relative conservation of the flanking sequence compared to READ1.
Figure 2
Figure 2
READ1 Binds the Transcription Factor ETV6 (A and B) SILAC results for Raji and HeLa cells and a two-dimensional interaction plot of enrichment for forward and reverse experiments. (C and D) ChIP results for the Raji (C) and Sk-N-MC (D) cell lines. “α-H3” is the positive-control antibody to a histone H3 variant enriched in actively transcribing genes, and “β-actin” is the control amplicon from ACTB, which encodes β-actin. Error bars represent the SD among three replicates. The single asterisk represents a p value below 0.05, and the double asterisks represents a p value below 0.01 (one-tailed t test; see Tables S6A and S6B).
Figure 3
Figure 3
The DCDC2 Risk Haplotypes Interact Synergistically with the KIAA0319 Risk Haplotype (A) Effect of genotype for the DCDC2 and KIAA0319 risk haplotypes on various reading, language, and cognitive phenotypes (described in detail in Table S1). Data points represent the mean of each group and were converted to a Z score relative to the mean of the ALSPAC sample population. Units of the y axis are fractions of a SD. Abbreviations are as follows: PD, phoneme-deletion task; Reading7, single-word reading at age 7 years; NW Reading, nonword reading at age 9 years; Spelling7 and Spelling9, spelling at ages 7 and 9 years, respectively; WOLD, Wechsler Objective Learning Dimensions verbal comprehension task; and NWR: nonword-repetition task. (B) Hypothetical model of differential effects of READ1 alleles. ETV6 monomers must at least homodimerize through their pointed (PNT) domains to bind DNA through their ETS domains, and they are thought to homopolymerize in vivo. Indels of READ1 repeat units could change the size of the ETV6 polymer and thus affect target-gene expression.
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