TY - JOUR
T1 - The aromatase gene CYP19A1
T2 - Several genetic and functional lines of evidence supporting a role in reading, speech and language
AU - Anthoni, Heidi
AU - Sucheston, Lara E.
AU - Lewis, Barbara A.
AU - Tapia-Páez, Isabel
AU - Fan, Xiaotang
AU - Zucchelli, Marco
AU - Taipale, Mikko
AU - Stein, Catherine M.
AU - Hokkanen, Marie Estelle
AU - Castrén, Eero
AU - Pennington, Bruce F.
AU - Smith, Shelley D.
AU - Olson, Richard K.
AU - Bruce Tomblin, J.
AU - Schulte-Körne, Gerd
AU - Nöthen, Markus
AU - Schumacher, Johannes
AU - Müller-Myhsok, Bertram
AU - Hoffmann, Per
AU - Gilger, Jeffrey W.
AU - Hynd, George W.
AU - Nopola-Hemmi, Jaana
AU - Leppanen, Paavo H T
AU - Lyytinen, Heikki
AU - Schoumans, Jacqueline
AU - Nordenskjöld, Magnus
AU - Spencer, Jason
AU - Stanic, Davor
AU - Boon, Wah Chin
AU - Simpson, Evan
AU - Mäkelä, Sari
AU - Gustafsson, Jan Åke
AU - Peyrard-Janvid, Myriam
AU - Iyengar, Sudha
AU - Kere, Juha
N1 - Funding Information:
Acknowledgments We wish to thank Juliana Bloom, Lisa Freeb-airn, Amy Hansen, Christopher Millard, Dmitry Leontiev, Carlin Miller for their assistance in data collection, Helge Neidt for sample handling, Kristina Duvefelt and Ingegerd Fransson for excellent genotyping and technical support as well as Margaret Warner for suggestions and support in the design and analysis of the ArKO mice experimental work. We also wish to express our appreciation to the speech-language pathologists who assisted us in recruiting participants and to the families who generously agreed to participate. This work was supported by the National Institutes of Health-National Institute on Deafness and Other Communication Disorders (NIH-NIDCD) grants to B.A.L, NIH-NIDCD to S.I., NIH-Eunice Kennedy Shriver Institute of Child Health and Human Development (NICHD) to G.W.H., NIH-NICHD 5P50-HD027802 to R.K.O. (with B.F.P. and S.D.S.), NIH-National Center for Research Resources (NCRR) to C.M.S., Sigrid Jusélius Foundation to J.K. and E.C., Academy of Finland to J.K., H.L. and E.C., Swedish Research Council to J.K., M.N. and M.P.-J., Swedish Cancer Fund to J.-Å.G. and J.K., Hjärn-fonden (Swedish Brain Foundation) to J.K. and I.T.-P., the Centennial Foundation of Helsingin Sanomat to H.A., the Päivikki and Sakari Sohlberg Foundation, the Swedish Royal Bank Tercentennial Foundation and Knut and Alice Wallenberg Foundation to J.K. This study was also supported by the European Union through the CASCADE Network of Excellence and the CRESCENDO Integrated Project; by a training grant (HL07567) from the National Heart, Lung and Blood Institute. The Colorado Learning Disabilities Research Center is also funded by NICHD (grant nr. 5P50HD027802). Some of the analyses were performed using the program package S.A.G.E. (2003 [Release 4.5]), which is supported by NIH-NCRR RR03655.
PY - 2012/7
Y1 - 2012/7
N2 - 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. Aromatasedeficient 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.
AB - 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. Aromatasedeficient 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.
KW - Categorical trait association
KW - Dyslexia
KW - Estrogen synthesis
KW - Quantitative trait analysis
KW - SLI
KW - SSD
KW - Translocation breakpoint
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U2 - 10.1007/s10519-012-9532-3
DO - 10.1007/s10519-012-9532-3
M3 - Article
C2 - 22426781
AN - SCOPUS:84864616724
SN - 0001-8244
VL - 42
SP - 509
EP - 527
JO - Behavior Genetics
JF - Behavior Genetics
IS - 4
ER -