TMEM127 – Renal Cell Carcinoma

TMEM127, encoding a transmembrane tumor suppressor, has been implicated in autosomal dominant predisposition to renal cell carcinoma (RCC) based on a single published case. A single individual with synchronous pheochromocytoma and multilocular clear cell RCC was found to carry a germline c.308del (p.Gly103fs) mutation, establishing initial evidence for TMEM127 involvement in RCC (one proband) (PMID:25800244). Cellular and molecular assays demonstrate that patient-derived TMEM127 variants, including those affecting transmembrane domains, abrogate membrane localization and internalization, consistent with loss-of-function via haploinsufficiency (PMID:32575117). No segregation data are available beyond the index case. While limited by the number of families, the mechanistic concordance of functional studies supports pathogenicity of TMEM127 variants in RCC. Larger cohorts and further familial studies are needed to confirm penetrance and variant spectrum. Key Take-home: Germline TMEM127 mutations should be considered in genetic testing for RCC predisposition, particularly in cases with concurrent pheochromocytoma and adrenergic catecholamine profiles.

References

• Virchows Archiv : an international journal of pathology • 2015 • Familial pheochromocytoma and renal cell carcinoma syndrome: TMEM127 as a novel candidate gene for the association. PMID:25800244
• The Journal of clinical endocrinology and metabolism • 2020 • Functional Characterization of TMEM127 Variants Reveals Novel Insights into Its Membrane Topology and Trafficking. PMID:32575117

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