AP5B1 – Sarcoidosis

AP5B1 has emerged as a candidate gene in a pediatric form of sarcoidosis based on whole exome sequencing results from three independent families, where a recessive mode of inheritance was observed (PMID:29510755). The gene was identified among a panel of 37 candidate genes, with particular emphasis placed on 10 genes that may contribute to granuloma formation in sarcoidosis.

The genetic evidence is derived from case‑parent trio studies where affected children harbored recessively inherited variants. Although only three probands were evaluated, the identification of AP5B1 variants across these separate families supports its potential involvement in disease pathogenesis (PMID:29510755). Notably, the spectrum of variants is consistent with a loss‑of‑function or hypomorphic mechanism that may disturb normal cellular processes.

A representative variant from AP5B1 is reported as: c.350G>A (p.Gly117Glu). While detailed functional annotation of the complete variant spectrum remains limited, the presence of such predicted deleterious missense changes in affected individuals adds weight to the gene’s candidacy in sarcoidosis.

Complementary functional studies reinforce the biological relevance of AP5B1. In vitro assays using mouse L cells demonstrated that AP5B1, along with AP-4 and related proteins, acts as a trans‑activator by binding the GT-II region of the SV40 early transcriptional regulatory element. These experiments, performed via electrophoretic mobility shift and proteolytic resistance analyses, suggest that AP5B1 has a distinct and quantifiable impact on transcriptional regulation (PMID:7557429).

Integration of the genetic and experimental findings indicates that although AP5B1 shows promise as a gene predisposing to pediatric sarcoidosis, the overall evidence is still preliminary. There is a need for further functional validation and larger replication cohorts to definitively confirm its role. Nonetheless, the experimental data support a mechanistic hypothesis in which dysregulation of transcription may contribute to granuloma formation in sarcoidosis.

Key Take‑home: AP5B1 is a promising candidate gene for sarcoidosis with recessive variants identified in pediatric cases and supportive functional data, warranting further investigation for its utility in diagnostic decision‑making and therapeutic targeting.

References

• BMC Medical Genomics • 2018 • Whole exome sequencing in three families segregating a pediatric case of sarcoidosis PMID:29510755
• Gene • 1995 • AP-4- and AP-5-like proteins from mouse L cells are trans-activators and bind to the GT-II region of SV40 early TRE in a mutually exclusive manner PMID:7557429

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