A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain

Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11553-8. doi: 10.1073/pnas.1833911100. Epub 2003 Sep 3.

Abstract

Approximately 3-10% of people have specific difficulties in reading, despite adequate intelligence, education, and social environment. We report here the characterization of a gene, DYX1C1 near the DYX1 locus in chromosome 15q21, that is disrupted by a translocation t(2;15)(q11;q21) segregating coincidentally with dyslexia. Two sequence changes in DYX1C1, one involving the translation initiation sequence and an Elk-1 transcription factor binding site (-3G --> A) and a codon (1249G --> T), introducing a premature stop codon and truncating the predicted protein by 4 aa, associate alone and in combination with dyslexia. DYX1C1 encodes a 420-aa protein with three tetratricopeptide repeat (TPR) domains, thought to be protein interaction modules, but otherwise with no homology to known proteins. The mouse Dyx1c1 protein is 78% identical to the human protein, and the nonhuman primates differ at 0.5-1.4% of residues. DYX1C1 is expressed in several tissues, including the brain, and the protein resides in the nucleus. In human brain, DYX1C1 protein localizes to a fraction of cortical neurons and white matter glial cells. We conclude that DYX1C1 should be regarded as a candidate gene for developmental dyslexia. Detailed study of its function may open a path to understanding a complex process of development and maturation of the human brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blotting, Southern
  • Brain / metabolism*
  • Chromosomes, Human, Pair 15
  • Cytoskeletal Proteins
  • DNA, Complementary
  • Dyslexia / genetics*
  • Female
  • Gene Expression Regulation*
  • Genetic Predisposition to Disease
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Molecular Sequence Data
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Pedigree
  • Polymorphism, Genetic
  • Repetitive Sequences, Amino Acid*
  • Sequence Homology, Amino Acid

Substances

  • Cytoskeletal Proteins
  • DNA, Complementary
  • DNAAF4 protein, human
  • Nerve Tissue Proteins
  • Nuclear Proteins

Associated data

  • GENBANK/AC013355
  • GENBANK/AF337549
  • GENBANK/AH012450
  • GENBANK/AH012451
  • GENBANK/AH012452
  • GENBANK/AH012453
  • GENBANK/AK005832
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