Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
The recurrent germline mutation in ADPRHL1, c.233A>T (p.Asp78Val) (PMID:35816343), has been identified in African American families affected by prostate cancer. Genetic analysis of 20 familial cases revealed that this rare non‑synonymous variant was present in four families, with clear evidence of co‑segregation in two families where additional affected relatives carried the mutation (PMID:35816343). This observation provides strong support for a direct association between ADPRHL1 and prostate cancer risk.
Further genetic evidence underscores the rarity and pathogenicity of this mutation. It was not detected in 170 unrelated healthy individuals, reinforcing its potential role in disease susceptibility. The segregation data, although limited to specific families, bolsters the evidence for a causative effect of the c.233A>T (p.Asp78Val) mutation in prostate cancer. This genetic data is critical for diagnostic decision‑making and risk assessment in high‑risk African American populations (PMID:35816343).
Functionally, the mutant ADPRHL1 protein has been shown to activate PARP1, which in turn increases the H2O2‑ or cisplatin‑induced DNA damage response. In benign prostate cells, this aberrant activation led to enhanced cell proliferation, whereas re‑expression of the wild‑type protein suppressed oncogenic growth. Notably, treatment with the PARP1 inhibitor olaparib was able to reverse these proliferative effects, providing mechanistic insight that aligns with the clinical phenotype of prostate cancer (PMID:35816343).
In addition to the genetic and cellular data specific to prostate cancer, functional assessment studies in other tissues have also been performed. For instance, an independent study in cardiomyocytes demonstrated that ADPRHL1 affects cellular adhesion and calcium signaling through the ROCK‑myosin II pathway (PMID:37880701). However, these findings do not conflict with the prostate cancer association but rather highlight the diverse roles of ADPRHL1 in different tissues.
Integrating the genetic and experimental findings, there is strong evidence supporting a pathogenic role for the ADPRHL1 c.233A>T (p.Asp78Val) mutation in prostate cancer. While additional data from multi‑patient analyses is available, the core evidence exceeds the ClinGen scoring maximum and substantiates the clinical utility of this marker for risk assessment and potential therapeutic targeting in affected individuals.
Key take‑home: Recognition of the ADPRHL1 recurrent germline mutation provides a valuable tool for targeted diagnostic evaluation and personalized treatment strategies in prostate cancer, particularly within high‑risk African American families.
Gene–Disease AssociationStrongRecurrent c.233A>T (p.Asp78Val) mutation observed in 4 independent AA families with prostate cancer, including co‑segregation in 2 families and absence in 170 controls (PMID:35816343). Genetic EvidenceStrongThe mutation was identified in multiple affected families with clear segregation and is absent in a large number of unaffected individuals, supporting its pathogenicity (PMID:35816343). Functional EvidenceStrongFunctional assays demonstrated that the ADPRHL1 mutant activates PARP1, increases DNA damage response, and promotes cell proliferation, while its effects are reversed by PARP1 inhibition (PMID:35816343). |