TMEM127 – Paraganglioma

TMEM127 encodes a transmembrane protein that functions as a tumor suppressor in chromaffin‐derived cells. Heterozygous germline variants in TMEM127 are associated with autosomal dominant predisposition to paraganglioma, a neuroendocrine tumor arising from paraganglia along the sympathetic and parasympathetic chains. The disease manifests predominantly as apparently sporadic, solitary abdominal or head-and-neck paragangliomas, often in adulthood. Genetic testing for TMEM127 should be considered in patients with paraganglioma after exclusion of more common susceptibility genes due to implications for family counseling and surveillance.

Genetic Evidence

TMEM127-related paraganglioma is inherited in an autosomal dominant manner with reduced penetrance and variable expressivity. To date, at least 23 unrelated probands across multiple cohorts have been reported with pathogenic or likely pathogenic TMEM127 variants ([PMID:23551308], [PMID:31781416], [PMID:22517554]). Segregation data are limited, although familial carriers have been identified. Case series and large screening studies identified both truncating and missense variants in 0.9–2% of paraganglioma cohorts, reaching the ClinGen genetic evidence cap for a Strong classification.

Variant Spectrum

A broad variant spectrum includes nonsense, frameshift, splice-site, and missense changes. Recurrent truncating variants such as c.415C>T (p.Gln139Ter) have been reported in sporadic paraganglioma ([PMID:23551308]). Other recurring defects include N-terminal frameshifts (e.g., c.86delG (p.Arg29LeufsTer52)) and C-terminal truncations. Missense variants cluster within predicted transmembrane domains and may impair membrane localization.

Functional Evidence

Cellular studies demonstrate that pathogenic TMEM127 variants lead to loss of membrane-binding ability, reduced protein stability, and defective endocytic internalization via clathrin-mediated pathways. An in-depth analysis revealed an unexpected fourth transmembrane domain and defined key acidic dileucine motifs required for proper trafficking ([PMID:32575117]). These concordant functional data support a loss-of-function mechanism underlying tumorigenesis.

Integration & Clinical Utility

Collectively, strong genetic and moderate experimental evidence establish TMEM127 as a paraganglioma susceptibility gene via haploinsufficiency. Multigene panel testing including TMEM127 enhances detection of hereditary risk in paraganglioma patients and informs individualized surveillance strategies. Key take-home: germline TMEM127 variants confer autosomal dominant risk for paraganglioma, warranting genetic testing to guide patient management and familial risk assessment.

References

• Internal Medicine Journal • 2013 • Novel mutation in the TMEM127 gene associated with phaeochromocytoma. PMID:23551308
• Case Reports in Endocrinology • 2019 • Novel TMEM127 Variant Associated to Bilateral Phaeochromocytoma with an Uncommon Clinical Presentation. PMID:31781416
• Hormone and Metabolic Research • 2012 • Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. PMID:22517554
• The Journal of Clinical Endocrinology and Metabolism • 2012 • TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. PMID:22419703
• 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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