Mtss2, also known as MTSS1L, encodes a protein that binds to plasma membranes, modulates their bending, and is highly expressed in the central nervous system (CNS) [1]. It belongs to the inverse BAR (I-BAR) domain proteins family, which sense and introduce outward membrane curvature, acting as a bridge between the cell membrane and the cytoskeleton [2]. Mtss2 is involved in activity-dependent synaptic plasticity, a crucial process in learning and memory [1].

The recurrent de novo c.2011C>T (p.Arg671Trp) missense variant in MTSS2 has been identified as causing syndromic intellectual disability. Individuals with this variant present with global developmental delay, mild intellectual disability, ophthalmological anomalies, microcephaly or relative microcephaly, and facial dysmorphisms [1]. Modeling this variant in Drosophila showed that the fly ortholog missing-in-metastasis (mim) is widely expressed in the CNS. Loss of mim led to reduced lifespan, impaired locomotor behavior, and reduced synaptic transmission. Expression of the human MTSS2 reference cDNA rescued the mim loss-of-function phenotypes, while the c.2011C>T variant had decreased rescue ability, suggesting it is a partial loss-of-function allele. Elevated expression of the variant led to similar defects as mim loss-of-function, indicating it may act as a dominant-negative allele [1].

In conclusion, Mtss2 plays a crucial role in neural function, especially in synaptic plasticity. The study of Mtss2 using genetic models like Drosophila has revealed its importance in normal neural development and how variants can lead to intellectual disability. Understanding Mtss2 is essential for uncovering the mechanisms underlying neurodevelopmental disorders [1].

References:

1. Huang, Yan, Lemire, Gabrielle, Briere, Lauren C, Boycott, Kym M, Bellen, Hugo J. 2022. The recurrent de novo c.2011C>T missense variant in MTSS2 causes syndromic intellectual disability. In American journal of human genetics, 109, 1923-1931. doi:10.1016/j.ajhg.2022.08.011. https://pubmed.ncbi.nlm.nih.gov/36067766/

2. Chatzi, Christina, Westbrook, Gary L. 2021. Revisiting I-BAR Proteins at Central Synapses. In Frontiers in neural circuits, 15, 787436. doi:10.3389/fncir.2021.787436. https://pubmed.ncbi.nlm.nih.gov/34975417/