Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

Baker, Emma; Butler, MG; Hartin, SN; Ling, L; Bui, M; Francis, D; Rogers, C; Field, MJ; Slee, J; Gamage, D; Amor, DJ; Godler, DE

doi:10.26181/5fd8196044fe5

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Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders

journal contribution

posted on 2020-12-15, 02:03 authored by Emma BakerEmma Baker, MG Butler, SN Hartin, L Ling, M Bui, D Francis, C Rogers, MJ Field, J Slee, D Gamage, DJ Amor, DE Godler

© 2020, The Author(s). Chromosome 15 (C15) imprinting disorders including Prader–Willi (PWS), Angelman (AS) and chromosome 15 duplication (Dup15q) syndromes are severe neurodevelopmental disorders caused by abnormal expression of genes from the 15q11–q13 region, associated with abnormal DNA methylation and/or copy number changes. This study compared changes in mRNA levels of UBE3A and SNORD116 located within the 15q11–q13 region between these disorders and their subtypes and related these to the clinical phenotypes. The study cohort included 58 participants affected with a C15 imprinting disorder (PWS = 27, AS = 21, Dup15q = 10) and 20 typically developing controls. Semi-quantitative analysis of mRNA from peripheral blood mononuclear cells (PBMCs) was performed using reverse transcription droplet digital polymerase chain reaction (PCR) for UBE3A and SNORD116 normalised to a panel of internal control genes determined using the geNorm approach. Participants completed an intellectual/developmental functioning assessment and the Autism Diagnostic Observation Schedule-2nd Edition. The Dup15q group was the only condition with significantly increased UBE3A mRNA levels when compared to the control group (p < 0.001). Both the AS and Dup15q groups also had significantly elevated SNORD116 mRNA levels compared to controls (AS: p < 0.0001; Dup15q: p = 0.002). Both UBE3A and SNORD116 mRNA levels were positively correlated with all developmental functioning scores in the deletion AS group (p < 0.001), and autism features (p < 0.001) in the non-deletion PWS group. The findings suggest presence of novel interactions between expression of UBE3A and SNORD116 in PBMCs and brain specific processes underlying motor and language impairments and autism features in these disorders.

Funding

This study was supported by the Victorian Government's Operational Infrastructure Support Programme, with the salaries supported by NHMRC project grants (Nos. 1049299 and 1103389 to D.E.G.); Murdoch Children's Research Institute, Royal Children's Hospital Foundation (D.E.G.); Next Generation Clinical Researchers Programme-Career Development Fellowship, funded by the Medical Research Future Fund (MRF1141334 to D.E.G.); the Financial Markets Foundation for Children (Australia; No. 2017-361 to D.E.G. and D.J.A.); the Genetics of Learning Disability (GOLD) Service (M.F.); the Foundation for Prader-Willi Syndrome Research, USA (grant Nos. 43445 and 501393 to D.E.G. and D.J.A., respectively); the National Institute of Child Health and Human Development (NICHD; grant No. HD02528 to M.G.B.); and joint funding from the Prader-Willi Syndrome Association (Australia), Foundation for Angelman Syndrome Therapeutics (Australia) and Dup15q Australia Ltd. The authors would like to thank all the study participants and their families for being involved in the study. We would also like to thank James O'Brien from the Prader-Willi Syndrome Association (Australia), Meagan Cross and Chloe Simons from the Foundation for Angelman Syndrome Therapeutics (Australia), and Chris Cahir from Dup15q Australia Ltd. for their assistance with the recruitment of participants.

History

Publication Date

2020-12-01

Journal

Translational Psychiatry

Volume

10

Issue

1

Article Number

362

Pagination

11p.

Publisher

Springer Nature

ISSN

2158-3188

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