Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients

EMBO Molecular Medicine

Elena Bonora⁴  Claudio Graziano⁴  Fiorella Minopoli⁴  Elena Bacchelli²  Pamela Magini⁴  Chiara Diquigiovanni⁴  Silvia Lomartire²  Francesca Bianco⁴  Manuela Vargiolu⁴  Piero Parchi¹  Elena Marasco⁵  Vilma Mantovani⁴  Luca Rampoldi⁸  Matteo Trudu⁸  Antonia Parmeggiani¹  Agatino Battaglia⁶  Luigi Mazzone³  Giada Tortora⁴  IMGSAC⁷  Elena Maestrini²  Marco Seri⁴ 

[1] Department of Neurology, University of Bologna, Bologna, Italy;Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy;Unit of Child Neuropsychiatry, IRCCS Ospedale Pediatrico Bambino Gesù, Roma, Italy;Unit of Medical Genetics, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy;CRBA, S. Orsola-Malpighi Hospital, Bologna, Italy;Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy;IMGSAC Institute of Neuroscience and Health and Society,, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK;Molecular Genetics of Renal Disorders Unit, Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy

关键词: autism spectrum disorders;    CADPS2;    intellectual disability;    monoallelic expression;    mutation screening;   

DOI  :  10.1002/emmm.201303235

来源: Wiley

【 摘 要 】

Abstract

Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.

Synopsis

Monoallelic and tissue-specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.

• Two rare variants of maternal origin (an intragenic deletion and a missense change) were identified in CADPS2 in a cohort of patients with neurodevelopmental abnormalities; the p. Asp1113Asn variant was shown to disrupt the interaction with dopamine receptor type 2 (D2DR).
• Differentially methylated sites were identified in CADPS2 first intron, in blood and amygdala, but they did not show a parent-of-origin methylation pattern typical of an imprinted gene.
• Tissue-specific, monoallelic maternal expression of CADPS2 in blood and in the amygdala plays a key role in regulating social interactions and supports the importance of a fine modulation of CADPS2 for human behavior.
• CADPS2 variants may contribute to intellectual disability and autism susceptibility, and their role should be interpreted in light of possible parent-of-origin effect.

【 授权许可】

CC BY   
© 2014 The Authors. Published under the terms of the CC BY license

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.