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Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach.

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Title: Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach.
Authors: Chiocchetti, A G, Kopp, M, Waltes, R, Haslinger, D, Duketis, E, Jarczok, T A, Poustka, F, Voran, A, Graab, U, Meyer, J, Klauck, S M, Fulda, S, Freitag, C M
Source: Molecular Psychiatry. Jul2015, Vol. 20 Issue 7, p839-849. 11p.
Subjects: Neurexins, Autism spectrum disorders, Gene expression, Cell differentiation, Transcription factors, Disease risk factors
Abstract: Contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin gene superfamily, is one of the best-replicated risk genes for autism spectrum disorders (ASD). ASD are predominately genetically determined neurodevelopmental disorders characterized by impairments of language development, social interaction and communication, as well as stereotyped behavior and interests. Although CNTNAP2 expression levels were proposed to alter ASD risk, no study to date has focused on its 5′ promoter. Here, we directly sequenced the CNTNAP2 5′ promoter region of 236 German families with one child with ASD and detected four novel variants. Furthermore, we genotyped the three most frequent variants (rs150447075, rs34712024, rs71781329) in an additional sample of 356 families and found nominal association of rs34712024G with ASD and rs71781329GCG[7] with language development. The four novel and the three known minor alleles of the identified variants were predicted to alter transcription factor binding sites (TFBS). At the functional level, the respective sequences spanning these seven variants were bound by nuclear factors. In a luciferase promoter assay, the respective minor alleles showed cell line-specific and differentiation stage-dependent effects at the level of promoter activation. The novel potential rare risk-variant M2, a G>A mutation −215 base pairs 5′ of the transcriptional start site, significantly reduced promoter efficiency in HEK293T and in undifferentiated and differentiated neuroblastoid SH-SY5Y cells. This variant was transmitted to a patient with autistic disorder. The under-transmitted, protective minor G allele of the common variant rs34712024, in contrast, increased transcriptional activity. These results lead to the conclusion that the pathomechanism of CNTNAP2 promoter variants on ASD risk is mediated by their effect on TFBSs, and thus confirm the hypothesis that a reduced CNTNAP2 level during neuronal development increases liability for ASD. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Variants of the CNTNAP2 5′ promoter as risk factors for autism spectrum disorders: a genetic and functional approach.
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  Data: <searchLink fieldCode="AR" term="%22Chiocchetti%2C+A+G%22">Chiocchetti, A G</searchLink><br /><searchLink fieldCode="AR" term="%22Kopp%2C+M%22">Kopp, M</searchLink><br /><searchLink fieldCode="AR" term="%22Waltes%2C+R%22">Waltes, R</searchLink><br /><searchLink fieldCode="AR" term="%22Haslinger%2C+D%22">Haslinger, D</searchLink><br /><searchLink fieldCode="AR" term="%22Duketis%2C+E%22">Duketis, E</searchLink><br /><searchLink fieldCode="AR" term="%22Jarczok%2C+T+A%22">Jarczok, T A</searchLink><br /><searchLink fieldCode="AR" term="%22Poustka%2C+F%22">Poustka, F</searchLink><br /><searchLink fieldCode="AR" term="%22Voran%2C+A%22">Voran, A</searchLink><br /><searchLink fieldCode="AR" term="%22Graab%2C+U%22">Graab, U</searchLink><br /><searchLink fieldCode="AR" term="%22Meyer%2C+J%22">Meyer, J</searchLink><br /><searchLink fieldCode="AR" term="%22Klauck%2C+S+M%22">Klauck, S M</searchLink><br /><searchLink fieldCode="AR" term="%22Fulda%2C+S%22">Fulda, S</searchLink><br /><searchLink fieldCode="AR" term="%22Freitag%2C+C+M%22">Freitag, C M</searchLink>
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  Data: Contactin-associated protein-like 2 gene (CNTNAP2), a member of the Neurexin gene superfamily, is one of the best-replicated risk genes for autism spectrum disorders (ASD). ASD are predominately genetically determined neurodevelopmental disorders characterized by impairments of language development, social interaction and communication, as well as stereotyped behavior and interests. Although CNTNAP2 expression levels were proposed to alter ASD risk, no study to date has focused on its 5′ promoter. Here, we directly sequenced the CNTNAP2 5′ promoter region of 236 German families with one child with ASD and detected four novel variants. Furthermore, we genotyped the three most frequent variants (rs150447075, rs34712024, rs71781329) in an additional sample of 356 families and found nominal association of rs34712024G with ASD and rs71781329GCG[7] with language development. The four novel and the three known minor alleles of the identified variants were predicted to alter transcription factor binding sites (TFBS). At the functional level, the respective sequences spanning these seven variants were bound by nuclear factors. In a luciferase promoter assay, the respective minor alleles showed cell line-specific and differentiation stage-dependent effects at the level of promoter activation. The novel potential rare risk-variant M2, a G>A mutation −215 base pairs 5′ of the transcriptional start site, significantly reduced promoter efficiency in HEK293T and in undifferentiated and differentiated neuroblastoid SH-SY5Y cells. This variant was transmitted to a patient with autistic disorder. The under-transmitted, protective minor G allele of the common variant rs34712024, in contrast, increased transcriptional activity. These results lead to the conclusion that the pathomechanism of CNTNAP2 promoter variants on ASD risk is mediated by their effect on TFBSs, and thus confirm the hypothesis that a reduced CNTNAP2 level during neuronal development increases liability for ASD. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Molecular Psychiatry is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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