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Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.

Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, Levitt P, Aldinger KA - Transl Psychiatry (2013)

Bottom Line: The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans.We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls.The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

View Article: PubMed Central - PubMed

Affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

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Sex-specific MET expression in postmortem brain of individuals with ASD. Samples are represented by open circles and group means are represented by horizontal bars. (a) MET expression in temporal cortex of females with RTT and controls (CTL). **P<0.001 (b) MET expression in temporal cortex of individuals with ASD and controls. (c) MET expression in the temporal cortex of individuals with ASD and controls as shown in panel b, separated by sex. No significant difference in MET expression was detected between males (M) and females (F) among controls. *P<0.05.
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fig4: Sex-specific MET expression in postmortem brain of individuals with ASD. Samples are represented by open circles and group means are represented by horizontal bars. (a) MET expression in temporal cortex of females with RTT and controls (CTL). **P<0.001 (b) MET expression in temporal cortex of individuals with ASD and controls. (c) MET expression in the temporal cortex of individuals with ASD and controls as shown in panel b, separated by sex. No significant difference in MET expression was detected between males (M) and females (F) among controls. *P<0.05.

Mentions: Few risk genes implicated in ASD have been directly examined in RTT cases. Thus, in order to translate the in vitro findings of a direct MeCP2-MET interaction, we assayed MET expression by qPCR in temporal cortex from age-matched RTT and control females (Figure 4a). Temporal cortex was used due to the enrichment of MET expression in this region of primate neocortex.15, 28, 40, 41MET expression was reduced dramatically in the temporal cortex of females with RTT compared with sex-matched controls (P=0.007).


Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome.

Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, Levitt P, Aldinger KA - Transl Psychiatry (2013)

Sex-specific MET expression in postmortem brain of individuals with ASD. Samples are represented by open circles and group means are represented by horizontal bars. (a) MET expression in temporal cortex of females with RTT and controls (CTL). **P<0.001 (b) MET expression in temporal cortex of individuals with ASD and controls. (c) MET expression in the temporal cortex of individuals with ASD and controls as shown in panel b, separated by sex. No significant difference in MET expression was detected between males (M) and females (F) among controls. *P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818007&req=5

fig4: Sex-specific MET expression in postmortem brain of individuals with ASD. Samples are represented by open circles and group means are represented by horizontal bars. (a) MET expression in temporal cortex of females with RTT and controls (CTL). **P<0.001 (b) MET expression in temporal cortex of individuals with ASD and controls. (c) MET expression in the temporal cortex of individuals with ASD and controls as shown in panel b, separated by sex. No significant difference in MET expression was detected between males (M) and females (F) among controls. *P<0.05.
Mentions: Few risk genes implicated in ASD have been directly examined in RTT cases. Thus, in order to translate the in vitro findings of a direct MeCP2-MET interaction, we assayed MET expression by qPCR in temporal cortex from age-matched RTT and control females (Figure 4a). Temporal cortex was used due to the enrichment of MET expression in this region of primate neocortex.15, 28, 40, 41MET expression was reduced dramatically in the temporal cortex of females with RTT compared with sex-matched controls (P=0.007).

Bottom Line: The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans.We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls.The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

View Article: PubMed Central - PubMed

Affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

ABSTRACT
Single nucleotide variants (SNV) in the gene encoding the MET receptor tyrosine kinase have been associated with an increased risk for autism spectrum disorders (ASD). The MET promoter SNV rs1858830 C 'low activity' allele is enriched in ASD, associated with reduced protein expression, and impacts functional and structural circuit connectivity in humans. To gain insight into the transcriptional regulation of MET on ASD-risk etiology, we examined an interaction between the methyl CpG-binding protein 2 (MeCP2) and the MET 5' promoter region. Mutations in MeCP2 cause Rett syndrome (RTT), a predominantly female neurodevelopmental disorder sharing some ASD clinical symptoms. MeCP2 binds to a region of the MET promoter containing the ASD-risk SNV, and displays rs1858830 genotype-specific binding in human neural progenitor cells derived from the olfactory neuroepithelium. MeCP2 binding enhances MET expression in the presence of the rs1858830 C allele, but MET transcription is attenuated by RTT-specific mutations in MeCP2. In the postmortem temporal cortex, a region normally enriched in MET, gene expression is reduced dramatically in females with RTT, although not due to enrichment of the rs1858830 C 'low activity' allele. We newly identified a sex-based reduction in MET expression, with male ASD cases, but not female ASD cases compared with sex-matched controls. The experimental data reveal a prominent allele-specific regulation of MET transcription by MeCP2. The mechanisms underlying the pronounced reduction of MET in ASD and RTT temporal cortex are distinct and likely related to factors unique to each disorder, including a noted sex bias.

Show MeSH
Related in: MedlinePlus