The Recurrent De Novo c.2011C>T Missense Variant in MTSS2 Causes Syndromic Intellectual Disability

Authors

Yan Huang
Gabrielle Lemire
Lauren C Briere
Fang Liu
Marja W Wessels
Xueqi Wang
Matthew Osmond
Oguz Kanca
Shenzhao Lu
Frances A High
Melissa A Walker
Lance H Rodan
Undiagnosed Diseases Network
Care4Rare Canada Consortium
Kristin D Kernohan
David A Sweetser
Kym M Boycott
Hugo J Bellen

Publication Date

10-6-2022

Journal

The American Journal of Human Genetics

DOI

10.1016/j.ajhg.2022.08.011

PMID

36067766

PMCID

PMC9606386

PubMedCentral® Posted Date

9-5-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, DNA, Complementary, Drosophila, Humans, Intellectual Disability, Membrane Proteins, Microcephaly, Microfilament Proteins, Mutation, Missense, Nervous System Malformations, Phenotype

Abstract

MTSS2, also known as MTSS1L, binds to plasma membranes and modulates their bending. MTSS2 is highly expressed in the central nervous system (CNS) and appears to be involved in activity-dependent synaptic plasticity. Variants in MTSS2 have not yet been associated with a human phenotype in OMIM. Here we report five individuals with the same heterozygous de novo variant in MTSS2 (GenBank: NM_138383.2: c.2011C>T [p.Arg671Trp]) identified by exome sequencing. The individuals present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and shared mild facial dysmorphisms. Immunoblots of fibroblasts from two affected individuals revealed that the variant does not significantly alter MTSS2 levels. We modeled the variant in Drosophila and showed that the fly ortholog missing-in-metastasis (mim) was widely expressed in most neurons and a subset of glia of the CNS. Loss of mim led to a reduction in lifespan, impaired locomotor behavior, and reduced synaptic transmission in adult flies. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function (LoF) phenotypes, whereas the c.2011C>T variant had decreased rescue ability compared to the reference, suggesting it is a partial LoF allele. However, elevated expression of the variant, but not the reference MTSS2 cDNA, led to similar defects as observed by mim LoF, suggesting that the variant is toxic and may act as a dominant-negative allele when expressed in flies. In summary, our findings support that mim is important for appropriate neural function, and that the MTSS2 c.2011C>T variant causes a syndromic form of intellectual disability.

Comments

This article has been corrected. See Am J Hum Genet. 2022 Nov 3;109(11):2092.