A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain.
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.
Taipale
Mikko
M
Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland.
Kaminen
Nina
N
Nopola-Hemmi
Jaana
J
Haltia
Tuomas
T
Myllyluoma
Birgitta
B
Lyytinen
Heikki
H
Muller
Kurt
K
Kaaranen
Minna
M
Lindsberg
Perttu J
PJ
Hannula-Jouppi
Katariina
K
Kere
Juha
J
D001483:Base Sequence; D015139:Blotting, Southern; D001921:Brain / Q000378:metabolism*; D002884:Chromosomes, Human, Pair 15; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D004410:Dyslexia / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D020449:Repetitive Sequences, Amino Acid; D017386:Sequence Homology, Amino Acid
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C478878:DNAAF4 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins