Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism

Young, Natalie; Asif, Maria; Jackson, Matthew; Fernández-Mayoralas, Daniel Martín; de la Peña, Mar Jimenez; Calleja-Pérez, Beatriz; Álvarez, Sara; Hunter-Featherstone, Eve; Noegel, Angelika A.; Höhne, Wolfgang; Nürnberg, Peter; Obara, Boguslaw; Hussain, Muhammad Sajid; Karakesisoglou, Iakowos; Fernández-Jaén, Alberto

Abstract

Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

Citation

Young, N., Asif, M., Jackson, M., Fernández-Mayoralas, D. M., de la Peña, M. J., Calleja-Pérez, B., …Fernández-Jaén, A. (2021). Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism. Genes, 12(9), Article 1294. https://doi.org/10.3390/genes12091294

• Journal Article Type: Article
• Acceptance Date: Aug 20, 2021
• Online Publication Date: Aug 24, 2021
• Publication Date: 2021-09
• Deposit Date: Jan 26, 2022
• Publicly Available Date: Jan 27, 2022
• Journal: Genes
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 9
• Article Number: 1294
• DOI: https://doi.org/10.3390/genes12091294
• Public URL: https://durham-repository.worktribe.com/output/1215995