Journal
BEHAVIOR GENETICS
Volume 42, Issue 4, Pages 509-527Publisher
SPRINGER
DOI: 10.1007/s10519-012-9532-3
Keywords
Dyslexia; SSD; SLI; Estrogen synthesis; Translocation breakpoint; Quantitative trait analysis; Categorical trait association
Funding
- National Institutes of Health-National Institute on Deafness and Other Communication Disorders (NIH-NIDCD) [5P50-HD027802]
- NIH-Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD)
- NIH-National Center for Research Resources (NCRR)
- Sigrid Juselius Foundation
- Academy of Finland
- Swedish Research Council
- Swedish Cancer Fund
- Hjarn-fonden (Swedish Brain Foundation)
- Centennial Foundation of Helsingin Sanomat
- Paivikki and Sakari Sohlberg Foundation
- Swedish Royal Bank Tercentennial Foundation
- Knut and Alice Wallenberg Foundation
- European Union through the CASCADE Network of Excellence
- CRESCENDO Integrated Project
- National Heart, Lung and Blood Institute [HL07567]
- NICHD [5P50HD027802]
- NIH-NCRR [RR03655]
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Inspired by the localization, on 15q21.2 of the CYP19A1 gene in the linkage region of speech and language disorders, and a rare translocation in a dyslexic individual that was brought to our attention, we conducted a series of studies on the properties of CYP19A1 as a candidate gene for dyslexia and related conditions. The aromatase enzyme is a member of the cytochrome P450 super family, and it serves several key functions: it catalyzes the conversion of androgens into estrogens; during early mammalian development it controls the differentiation of specific brain areas (e.g. local estrogen synthesis in the hippocampus regulates synaptic plasticity and axonal growth); it is involved in sexual differentiation of the brain; and in songbirds and teleost fishes, it regulates vocalization. Our results suggest that variations in CYP19A1 are associated with dyslexia as a categorical trait and with quantitative measures of language and speech, such as reading, vocabulary, phonological processing and oral motor skills. Variations near the vicinity of its brain promoter region altered transcription factor binding, suggesting a regulatory role in CYP19A1 expression. CYP19A1 expression in human brain correlated with the expression of dyslexia susceptibility genes such as DYX1C1 and ROBO1. Aromatase-deficient mice displayed increased cortical neuronal density and occasional cortical heterotopias, also observed in Robo1-/- mice and human dyslexic brains, respectively. An aromatase inhibitor reduced dendritic growth in cultured rat neurons. From this broad set of evidence, we propose CYP19A1 as a candidate gene for human cognitive functions implicated in reading, speech and language.
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