Scientific article
OA Policy
English

Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders

Published inGenetics in medicine, vol. 23, no. 10, p. 1912-1921
First online date2021-06-10
Abstract

Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants.

Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins.

Results: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein-protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1.

Conclusion: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders.

Keywords
  • HEK293 Cells
  • Humans
  • Nerve Tissue Proteins / genetics
  • Neurodevelopmental Disorders / genetics
  • Neurons
  • Phenotype
  • Exome Sequencing
Citation (ISO format)
MAY, Halie J et al. Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders. In: Genetics in medicine, 2021, vol. 23, n° 10, p. 1912–1921. doi: 10.1038/s41436-021-01222-w
Main files (1)
Article (Accepted version)
accessLevelPublic
Secondary files (1)
Identifiers
Journal ISSN1098-3600
56views
11downloads

Technical informations

Creation03/10/2022 14:50:45
First validation28/08/2023 07:58:32
Update time28/08/2023 07:58:32
Status update28/08/2023 07:58:32
Last indexation01/11/2024 05:53:44
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack