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The association between PPP2R5B and multiple endocrine neoplasia type 1 (MEN1) has been a subject of investigation over the past decades. Initial genomic mapping studies of the 11q13 region, in which MEN1 resides, included PPP2R5B as part of a candidate gene cluster. These studies provided early evidence for a potential involvement of PPP2R5B in the MEN1 locus based on its positional proximity (PMID:9286704). The mapping strategy utilized a 1.2-Mb sequence-ready contig that helped delineate the gene-rich region associated with MEN1. Although this early evidence raised interest, it was largely based on genomic localization rather than causative variant discovery. As such, the initial findings offered limited resolution regarding the role of PPP2R5B in disease pathogenesis.
Subsequent studies aimed at identifying the causative gene for MEN1 provided refined genetic analysis in multiple families. In one such study, mutation screening in 10 unrelated MEN1 families was performed to detect pathogenic variants in candidate genes. In the process, two candidates, including PPP2R5B, were specifically excluded from being the MEN1 gene based on the absence of disease‐segregating mutations (PMID:9215690). This study, which identified SCG2 as the true MEN1 gene, highlighted that no reproducible pathogenic variants in PPP2R5B were observed. The lack of co‐segregation of potential pathogenic PPP2R5B variants with the MEN1 phenotype strongly undermines its candidacy. Thus, the negative genetic findings have cast doubt on an unequivocal association between PPP2R5B and MEN1.
When examining the genetic evidence in further detail, no specific pathogenic coding variant in PPP2R5B has been reported in the context of MEN1. The variant spectrum for PPP2R5B remains unestablished because available studies did not document any reproducible HGVS‐described mutations (e.g., a variant like c.123A>T (p.Lys41Asn)) in this gene for MEN1 cases. Additionally, there is no evidence of recurrent or founder mutations involving PPP2R5B in MEN1 cohorts. The absence of such variants from comprehensive case series further supports a conclusion of limited genetic evidence. The available data suggest that even though PPP2R5B was initially captured within the critical region, its mutational profile does not support a causative role in MEN1. Consequently, the genetic evidence remains insufficient for clinical validation.
The functional studies evaluating the PP2A regulatory subunits provide important context for PPP2R5B’s cellular role. Members of the B56 family, including PPP2R5B, have been shown to regulate PP2A activity, affecting processes such as cell growth and differentiation (PMID:8703017). However, these studies focus on the general biology of PP2A regulatory mechanisms and do not offer direct evidence linking PPP2R5B dysfunction to the tumorigenesis observed in MEN1. In parallel, additional studies on the genomic organization and regulation of the PP2A complex (PMID:15095873) support the functional heterogeneity of B56 subunits without specifically implicating PPP2R5B. Therefore, the experimental data are not concordant with a pathogenic mechanism for MEN1 that is mediated by PPP2R5B. In summary, while functional assays underscore the importance of PP2A subunit regulation, they do not resolve the uncertainty regarding the gene’s role in MEN1.
Integrating the genetic mapping evidence with the negative findings from mutation screening and the inconclusive functional data, the overall association between PPP2R5B and MEN1 remains disputed. The initial inclusion based on genomic colocalization has been offset by subsequent exclusion through targeted mutation analysis. No segregation with disease, no well‐documented pathogenic variant, and a lack of functional studies specifically linking PPP2R5B to MEN1 pathology have been observed. This conflicting evidence emphasizes the need for cautious interpretation and underscores that additional, robust data are necessary before a clinical role for PPP2R5B in MEN1 can be accepted. As such, the current literature does not support the clinical utilization of PPP2R5B as a diagnostic marker for MEN1.
Key Take‑home Sentence: Despite early genomic co‑localization, the exclusion of PPP2R5B in mutation analyses and the absence of direct functional evidence result in a disputed association with MEN1, limiting its current clinical utility for diagnosis.
Gene–Disease AssociationDisputedAlthough early mapping studies placed PPP2R5B within the critical MEN1 region (PMID:9286704), subsequent mutation analyses in 10 unrelated MEN1 families excluded it as disease‐causing (PMID:9215690). Genetic EvidenceLimitedNo pathogenic variants in PPP2R5B have been reproducibly identified in MEN1 patients; variant screening and segregation analyses failed to support its role. Functional EvidenceLimitedFunctional studies of PP2A regulatory subunits indicate important cellular roles but do not provide specific evidence for a pathogenic mechanism involving PPP2R5B in MEN1. |