AP1S2 – X-linked Intellectual Disability

AP1S2 is a critical gene involved in clathrin‐mediated vesicular trafficking, and multiple independent studies have demonstrated that loss‑of‑function alterations in this gene are strongly associated with X‑linked intellectual disability (PMID:17186471). The clinical findings across several reports include variable degrees of intellectual impairment, delayed speech and motor development, and additional neurological features such as hypotonia and spasticity, which are consistent with a syndromic presentation of X‑linked intellectual disability (PMID:22210230).

Case‑report data include a notable instance of a 495 Kb deletion encompassing AP1S2 as well as multiple point and splice‑site mutations. In one family, a novel splice‑site mutation was identified and characterized as causing leaky splicing with aberrant transcripts, lending support to a pathogenic mechanism driven by disruption of normal AP1S2 function (PMID:38682877).

Genetic evidence is robust; several independent studies have reported AP1S2 alterations, such as the recurrent nonsense mutation c.154C>T (p.Arg52Ter), which have been identified in multiple unrelated families. A literature review encompassed at least 51 patients with AP1S2 pathogenic variants, underscoring the gene’s critical role in the etiology of X‑linked intellectual disability (PMID:38682877).

Segregation analyses further strengthen the association, with affected pedigrees demonstrating that the mutation co‑segregates with the disease phenotype across several generations. In one multi‑generation family, there were seven affected individuals exhibiting similar neurodevelopmental features, providing clear segregation data to support the pathogenic role of AP1S2 alterations (PMID:30714330).

Experimental investigations have contributed important functional evidence. mRNA analysis, splicing assays, and biomarker studies consistently demonstrate that AP1S2 mutations disrupt normal protein production and vesicle trafficking. Although the cellular models confirm the predicted loss‑of‑function mechanism, these experimental findings are classified as moderate due to the inherent challenges of replicating the complex neuronal context in vitro (PMID:30714330).

Considering the convergence of genetic, segregation, and functional data from multiple independent studies, the association between AP1S2 and X‑linked intellectual disability is robust and clinically actionable. This integrated evidence underpins the use of AP1S2 genetic testing in diagnostic workflows and affirms its utility for precision medicine initiatives.

References

• European journal of medical genetics • 2012 • Deletion of the AP1S2 gene in a child with psychomotor delay and hypotonia PMID:22210230
• American journal of human genetics • 2006 • Mutations in the gene encoding the Sigma 2 subunit of the adaptor protein 1 complex, AP1S2, cause X‑linked mental retardation PMID:17186471
• American journal of human genetics. Part A • 2024 • A novel AP1S2 variant causing leaky splicing in X‑linked intellectual disability: Further delineation and intrafamilial variability PMID:38682877
• Brain and behavior • 2019 • A novel splice site mutation in AP1S2 gene for X‑linked mental retardation in a Chinese pedigree and literature review PMID:30714330

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