Characterisation of a rare ATP2C2 missense variant associated with language impairment

Abstract

Developmental language disorder (DLD) is a common condition diagnosed when children show unexpected difficulties in expressing and understanding spoken language. DLD is highly heritable (~70%) and affects up to 8% of pre-school children in the UK. Only a few genetic factors have been reported so far. Among those, ATP2C2 is a strong candidate supported by associations with both common and rare variants. Through an exome sequencing analysis, we identified a rare non-synonymous variant (rs78887288) in ATP2C2, a gene encoding for a Ca²⁺ and Mn²⁺ transporter.

I followed this finding up by genotyping rs78887288 in individuals selected for language related disorders. I found that the rare allele increases the risk for language impairment in clinical samples (N = 360) and is associated with more general cognitive abilities in a population-based cohort. By data mining from public repositories and the application of molecular biological techniques, I evaluated the expression of this gene at the transcript and protein level and explored its subcellular distribution. I showed that ATP2C2 is expressed in fetal and adult brain supporting a contribution of this gene in the nervous system. I showed that the encoded protein localises along the secretory pathway supporting its role in Ca²⁺ storage and Mn²⁺ detoxification. The rs78887288 variant causes the substitution of an amino acid. By coupling in silico predictions and functional assays, I investigated the potential impact of this change on the protein activity. My findings suggested that the variant exerts a subtle effect on the ATPase activity and ion selectivity of the transporter.

While genetic mapping is necessary to identify risk factors, functional characterisation is essential to understand the underlying molecular mechanisms contributing to diseases. Here I combined different methodologies to build an experimental framework that can be used to study candidate genes for neurodevelopmental disorders.

Date of Award	2 Jul 2021
Original language	English
Awarding Institution	University of St Andrews
Supervisor	Silvia Paracchini (Supervisor) & Samantha J. Pitt (Supervisor)