HGNC Approved Gene Symbol: TMEM127
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38): 2:96,248,514-96,265,997 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11.2 | {Pheochromocytoma, susceptibility to} | 171300 | Autosomal dominant | 3 |
Qin et al. (2010) identified the TMEM127 gene by positional cloning of a locus on chromosome 2q11 identified through a family with autosomal dominant inheritance of pheochromocytoma (171300). The TMEM127 protein contains 238 amino acids with 3 predicted transmembrane domains and shares 98.7% and 85.2% amino acid identity with mouse and zebrafish protein, respectively. Northern blot analysis of human tissues showed most abundant expression of 4.2-, 3.8-, and 3.1-kb transcripts in heart, brain, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, small intestine, and colon. TMEM127 expression was also found in a variety of epithelial cancer cell lines, including those derived from brain, breast, colon, prostate, and liver. Mouse Tmem127 showed ubiquitous expression in all mouse tissues examined at 1 month and 5 months of age. Immunoblot assay detected TMEM127 as a 26-kD band in transfected HEK293 cells. Confocal microscopy observed TMEM127 localized to the plasma membrane and the cytoplasm, both in a punctate pattern and as perinuclear clusters. Colocalization studies showed that TMEM127 associated with a subpopulation of vesicular organelles corresponding to early endosomal structures, with the Golgi, and with lysosomes, suggesting that TMEM127 associates dynamically with endosomes and may participate in protein trafficking between these structures.
Qin et al. (2010) determined that the TMEM127 gene contains 4 exons.
Qin et al. (2010) stated that the TMEM127 gene maps to chromosome 2q11.
Qin et al. (2010) showed that TMEM127 depletion did not affect AKT (164730) activation or phosphorylation but did result in increased phosphorylation of 4EBP1 (EIF4EBP1; 602223) in HEK293, A2058, and HeLa cells. In TMEM127-transfected 293E cells, TMEM127 expression resulted in reduced mTORC1 complex signaling (see 601231). Further studies showed that TMEM127-mutant tumors showed hyperphosphorylation of S6K1 (RPS6KB1; 608938), which is an mTOR effector protein. RNAi-knockdown of TMEM127 resulted in increased phosphorylation of the mTORC1 target S6K1 in 293E cells under both amino acid-starved and amino acid-rich conditions. TMEM127 localized to the same compartment as that of amino-acid activated mTOR, suggesting that the effects of TMEM127 on mTOR may be compartment-specific and may influence mTOR subcellular localization. Qin et al. (2010) suggested that TMEM127 limits mTORC1 activation and that it occupies the same intracellular domain as active mTOR.
Qin et al. (2010) identified 7 different heterozygous mutations in the TMEM127 gene (see, e.g., 613403.0001-613403.0004) in 7 unrelated probands with pheochromocytoma (171300). Six of the mutations were truncating mutations, consistent with a loss of function. All tumors examined showed loss of heterozygosity at the TMEM127 locus, suggesting a classic mechanism of the 2-hit model of tumor suppressor inactivation. Four of the probands had a family history of pheochromocytoma. The average age of onset was 45.3 years, and all tumors arose from the adrenal medulla with 3 patients having bilateral tumors. Overall, mutations were found in about 30% of familial cases and 3% of sporadic cases. Microarray-based expression profiling showed that the transcription signature of TMEM127-mutant tumors was increased in kinase receptor signals, similar to pheochromocytomas due to NF1 (162200) and RET (164761) mutations. This was in contrast to the expression profiles of pheochromocytomas with mutations in the VHL (608537), SDHB (185470), or SDHD (602690) genes, which were uniquely enriched in transcripts involved in response to hypoxia.
In 7 members of a family with autosomal dominant inheritance of pheochromocytoma (171300), originally reported by Dahia et al. (2005), Qin et al. (2010) identified a heterozygous germline A-to-C transversion in intron 3 of the TMEM127 gene, resulting in a frameshift and premature termination. Two affected individuals from another unrelated family carried the same mutation, but haplotype analysis excluded a common ancestor. Analysis of all tumor tissues showed loss of heterozygosity at the TMEM127 locus, consistent with a 2-hit model of tumor suppressor inactivation. Age at onset ranged from 34 to 54 years in the first family and from 34 to 42 years in the second family. TMEM127 expression was decreased, consistent with a loss of function.
Toledo et al. (2015) offered genetic counseling, testing, and follow-up to 151 members of the 6-generation family carrying the c.410-2A-C mutation studied by Qin et al. (2010) and Dahia et al. (2005). Forty-seven individuals were found to carry the mutation. Clinical data were available for 34 mutation-positive individuals who were followed for 1 to 20 years (mean 8.7 years). Pheochromocytoma was diagnosed in 11 (32%) at a median age of 43 years. Two patients were asymptomatic, and 9 had symptoms starting on average at age 29 (range 10-55 years). Tumors were multicentric in 5 and bilateral in 5 patients. Over half had at least 1 adrenomedullary nodule less than 10 mm. No paragangliomas, distant metastases, or other manifestations were reported.
In 2 members of a family with pheochromocytoma (171300), Qin et al. (2010) identified a heterozygous 475C-T germline transition in the TMEM127 gene, resulting in a gln159-to-ter (Q159X) substitution. Analysis of tumor tissue showed loss of heterozygosity at the TMEM127 locus, consistent with a 2-hit model of tumor suppressor inactivation. Age at onset was 49 and 72 years, respectively, and both patients had bilateral tumors. TMEM127 expression was decreased, consistent with a loss of function.
In 2 members of a family with pheochromocytoma (171300), Qin et al. (2010) identified a heterozygous germline G-to-T transversion in intron 2 of the TMEM127 gene, resulting in a frameshift and premature termination. Analysis of tumor tissue showed loss of heterozygosity at the TMEM127 locus, consistent with a 2-hit model of tumor suppressor inactivation. Age at onset was 54 and 66 years, respectively, and both patients had bilateral tumors. TMEM127 expression was decreased, consistent with a loss of function.
In a patient who developed a pheochromocytoma (171300) at age 25 years, Qin et al. (2010) identified a heterozygous germline 1-bp insertion (150insA) in the TMEM127 gene, resulting in a frameshift and premature termination. Analysis of tumor tissue showed loss of heterozygosity at the TMEM127 locus, consistent with a 2-hit model of tumor suppressor inactivation. TMEM127 expression was decreased, consistent with a loss of function.
Dahia, P. L. M., Hao, K., Rogus, J., Colin, C., Pujana, M. A. G., Ross, K., Magoffin, D., Aronin, N., Cascon, A., Hayashida, C. Y., Li, C., Toledo, S. P. A., Stiles, C. D. Novel pheochromocytoma susceptibility loci identified by integrative genomics. Cancer Res. 65: 9651-9658, 2005. [PubMed: 16266984] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-1427]
Qin, Y., Yao, L, King, E. E., Buddavarapu, K., Lenci, R. E., Chocron, E. S., Lechleiter, J. D., Sass, M., Aronin, N., Schiavi, F., Boaretto, F., Opocher, G., Toledo, R. A., Toledo, S. P. A., Stiles, C., Aguiar, R. C. T., Dahia, P. L. M. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nature Genet. 42: 229-233, 2010. [PubMed: 20154675] [Full Text: https://doi.org/10.1038/ng.533]
Toledo, S. P. A., Lourenco, D. M., Jr., Sekiya, T., Lucon, A. M., Baena, M. E. S., Castro, C. C., Bortolotto, L. A., Zerbini, M. C. N., Siqueira, S. A. C., Toledo, R. A., Dahia, P. L. M. Penetrance and clinical features of pheochromocytoma in a six-generation family carrying a germline TMEM127 mutation. J. Clin. Endocr. Metab. 100: E308-E318, 2015. Note: Electronic Article. [PubMed: 25389632] [Full Text: https://doi.org/10.1210/jc.2014-2473]