Relevance to Autism

Analysis of whole-exome sequencing data from 13,091 individuals diagnosed with autism recruited from the SSC, SPARK, and iPSYCH cohorts, 19,488 first-degree relatives of individuals with autism from the SSC and SPARK cohorts, and 194,070 individuals identified from unselected population samples from the iPSYCH and UK Biobank cohorts in Rolland et al., 2023 identified AP2M1 as a novel ASD candidate gene intolerant to loss-of-function variants with an odds ratio greater than 10. Several de novo variants in the AP2M1 gene, includiing a de novo loss-of-function variant and multiple de novo missense variants, have been identified in ASD probands (Yuen et al, 2017; Satterstrom et al., 2020; Zhou et al., 2022; Wang et al., 2023). A recurrent de novo missense variant in the AP2M1 gene (p.Arg170Trp) that resulted in impaired clathrin-mediated endocytosis was found to be responsible for a form of autosomal dominant intellectual disability (MRD60; OMIM 618587) in four unrelated females in Helbig et al., 2019; all four females presented with global developmental delay, moderate-severe intellectual disability, and seizures, and two of the four individuals with this disorder were also diagnosed with autism spectrum disorder.

Molecular Function

This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein.

External Links

References