The emerging role of ER-localized TMEM proteins in neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) comprise a spectrum of conditions that impair brain development and nervous system function, resulting in lifelong cognitive, behavioral, and motor disabilities. Globally, more than 3% of children are affected by NDDs. Although advances in next-generation sequencing technology have identified many disease-associated genes, the cellular and molecular mechanisms underlying NDD pathogenesis remain poorly understood. Recent genomic and clinical studies have highlighted the transmembrane (TMEM) family of proteins as emerging contributors to NDDs. TMEM proteins represent a structurally and functionally diverse group that localize to membranes of various cellular organelles, including the endoplasmic reticulum (ER). Several ER-resident TMEM proteins have been increasingly implicated in neurodevelopmental impairments, suggesting a critical role for ER-associated processes in brain development and function. In this review, we describe the key ER-resident TMEM proteins and their association with neurodevelopmental disorders. We discuss the known cellular functions of these proteins, summarize evidence linking their dysfunction to neurodevelopmental phenotypes, and highlight emerging mechanisms by which ER-resident TMEM proteins may contribute to NDD pathogenesis. Finally, we outline key knowledge gaps and discuss how elucidating the functions of these proteins may provide new insights into disease etiology.