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. 2012 Jul;42(4):509-27.
doi: 10.1007/s10519-012-9532-3. Epub 2012 Mar 17.

The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language

Heidi Anthoni  1 , Lara E Sucheston, Barbara A Lewis, Isabel Tapia-Páez, Xiaotang Fan, Marco Zucchelli, Mikko Taipale, Catherine M Stein, Marie-Estelle Hokkanen, Eero Castrén, Bruce F Pennington, Shelley D Smith, Richard K Olson, J Bruce Tomblin, Gerd Schulte-Körne, Markus Nöthen, Johannes Schumacher, Bertram Müller-Myhsok, Per Hoffmann, Jeffrey W Gilger, George W Hynd, Jaana Nopola-Hemmi, Paavo H T Leppanen, Heikki Lyytinen, Jacqueline Schoumans, Magnus Nordenskjöld, Jason Spencer, Davor Stanic, Wah Chin Boon, Evan Simpson, Sari Mäkelä, Jan-Åke Gustafsson, Myriam Peyrard-Janvid, Sudha Iyengar, Juha Kere
Affiliations

The aromatase gene CYP19A1: several genetic and functional lines of evidence supporting a role in reading, speech and language

Heidi Anthoni et al. Behav Genet. 2012 Jul.

Abstract

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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Figures

Fig. 1
Fig. 1
FISH detecting the t(2;15)(p12;q21) with chromosome 2- and 15-specific BAC probes, on metaphases from a dyslexic individual. a Chromosome 2 probe, BAC clone RP11-521O14, shows hybridization signals on chromosomes 2, der(2), and der(15) (red). Probe RP11-236I9, distal to the breakpoint, hybridizes only to chromosome 2 and der(15) (green). b Chromosome 15 probe, BAC clone RP11-108K3, shows hybridization signals on chromosomes 15, der(15), and der(2) (green)
Fig. 2
Fig. 2
The CYP19A1 locus on 15q21.2. a An overall map of chromosome 15q shows the relative positions of CYP19A1, DYX1C1 and the linkage peaks in different studies of dyslexia (solid lines) and SSD (double lines). b CYP19A1 gene organization, including coding exons (vertical bars), promoter regions (arrowheads), and the translocation t(2;15)(p12;q21) breakpoint (slash). The brain-specific exon/promoter I.f is highlighted with a thicker arrowhead. The gene is located on the reverse strand and therefore is drawn from right (5′) to left (3′). c An evolutionary comparison of the CYP19A1 genomic sequence across four species (dog, mouse, opossum and frog) shows the highest conservation for the brain-specific exon/promoter I.f. The 20 SNPs genotyped in this study are positioned along the gene on the lowest part of the evolutionary sequence comparison. The two SNPs flanking I.f and used in EMSA experiments are indicated by thick red arrows. Colored stars under SNPs are indicating a significantly associated QT to the corresponding marker. In the OH, US, SSD cohort, association to QTs such as phonological processing, oral motor skills and language, is marked with blue, green and yellow stars, respectively. Red stars indicate association to reading measures detected in the GA, US, DYS cohort. d Haplotypes associated with dyslexia as a categorical trait in three of the cohorts and the respective LD structures
Fig. 3
Fig. 3
EMSA showing the effects, on transcription factor binding, of the human-specific variant from exon/promoter I.f of CYP19A1 (a) as well as the effect of the two SNPs (rs11632903 and rs1902586) flanking I.f (b). Nuclear extracts (NE) and whole cell extracts (WCE) from the neuroblastoma cell line SH-SY5Y were used in EMSA. The specificity of all probes was confirmed by competition assays (Comp) with unlabeled probes (shown only in a). A “+” in the top of the EMSAs denotes the type of extracts and presence in the extracts of antibodies for supershifts or probes for competitions. a EMSA for the human-specific variant from exon/promoter I.f. Arrows show differences in retardation patterns for the human- (T) and the primate- (C) specific alleles. b EMSA for the two genotyped SNPs flanking I.f; C and T denote the alleles of rs11632903 and G and A of rs1902586, respectively. Predicted altered bindings of TFII-I and Elk-I to rs11632903 were verified by supershift assays (black and white filled arrowheads respectively) with specific antibodies, in WCE and by a consensus probe (SRE) to compete with the TFII-I binding site
Fig. 4
Fig. 4
Correlation of CYP19A1 (y-axis) mRNA expression to four dyslexia genes (ROBO1, DYX1C1, DCDC2, and KIAA0319; x-axis, respectively) in different regions of adult human brain. X- and y-axes are in arbitrary log2 units. For clarity, the scales are not shown. 1 thalamus; 2 hypothalamus; 3 paracentral gyrus; 4 hippocampus; 5 temporal cortex; 6 frontal cortex; 7 parietal cortex; 8 occipital cortex; 9 postcentral gyrus; 10 whole brain
Fig. 5
Fig. 5
Testosterone enhances neuronal process outgrowth in an aromatase-dependent manner. E17 rat embryonic hippocampal neurons cultured for 4 days with testosterone (a) or with testosterone and the aromatase inhibitor letrozole (b), and stained with the neuronal marker TuJ1 (red). c Total neurite outgrowth in μm/neuron. The measurement shows the effects of solvent (CO), testosterone (T), letrozole (L), estradiol-17β (E). Letrozole inhibited testosterone-induced outgrowth (L+T), but did not inhibit the effects of estradiol-17β and testosterone together (L+T+E). Letrozole alone had no significant effects on neurite outgrowth. Similar effects were observed with a 3-day treatment (data not shown). *P < 0.05 against control, # P < 0.05 against T and L+T+E (ANOVA followed by t-test)
Fig. 6
Fig. 6
Cortical disorganization in ArKO mice as compared to WT. Increased neuronal density (a) and EGF signal (b) at E17.5 in the somatosensory cortex of ArKO mice vs. WT. Increased neuronal density (c) and parvalbumin-positive interneurons (d) in 5 months-old male ArKO mice vs. WT. (a cell body in blue; b EGF-positive cells in red; c neurons (NeuN-positive) in red; d parvalbumin-positive interneuron in red). (e) Mean number of parvalbumin-positive interneurons in the layers II–VI of the somatosensory cortex in 5 months-old male ARKO mice. (f) Mean number of NeuN positive neurons in the layers II–VI of the somatosensory cortex in 5 months-old male ArKO and WT. Student’s t-test: *P < 0.05; **P < 0.01. Scale bars a 50 μm; b 50 μm; c and d 200 μm
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