Molecular and phenotypic evaluation of a novel germline TMEM127 mutation with an uncommon clinical presentation

Deng, Yilun; Flores, Shahida K.; Cheng, Zi Ming; Qin, Yuejuan; Schwartz, R C; Malchoff, Carl D.; Dahia, Patricia L.M.

doi:10.1530/erc-17-0359e

Cited by 5 publications

(14 citation statements)

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“…The majority of these mutation carriers develop (bilateral) PCC, but extra‐adrenal PGL and head and neck paraganglioma (HNPGL) may also occur. According to the current literature, the median age at presentation of disease is 44 years, with a range from 16 to 80 years of age . This is clearly older than the median age at diagnosis in other PCC/PGL‐associated germline mutation carriers and is more comparable with the age distribution of sporadic PCC/PGL.…”

Section: Discussionmentioning

confidence: 92%

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Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas

et al. 2018

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Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.

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Section: Discussionmentioning

confidence: 92%

“…Malignant PCC/PGL, defined as the presence of metastases, seems to be very rare . Renal cell carcinomas, however, have been described in patients with TMEM127 germline mutations . The optimal follow‐up and surveillance for mutation carriers has not been established yet.…”

Section: Discussionmentioning

confidence: 99%

Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas

et al. 2018

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“…An MSCV construct which generates TMEM127-WT fused to a Flag tag at its C-terminal (TMEM127-Flag) combined with a biscistronic GFP reporter was also used. These constructs were transiently transfected into HEK293FT cells (ATCC) CRISPR/Cas9-edited to knockout TMEM127 (TMEM127 KO) as we previously reported 11 . Transfections were performed using Lipofectamine 2000 (Invitrogen) according to the manufacturer's recommendations.…”

Section: Plasmids Cell Culture and Transfectionsmentioning

confidence: 99%

“…We had previously observed that pathogenic TMEM127 variant proteins were undetectable by Western blot, implying potential instability and premature degradation 7,8,11,13 . We established WT construct expression over a time course of 24, 48 and 72h after transfection in HEK293FT cells that we previously engineered to lack TMEM127 11 (Fig.…”

Section: Variability In Expression Levels Of Germline Tmem127 Variantsmentioning

confidence: 99%

“…As a recognized tumor suppressor gene with Tier 1 status in the COSMIC Cancer Gene Census (COSMIC v90) and as a PHEO/PGL/RCC susceptibility gene, TMEM127 has been included in several commercially available and research-based hereditary cancer genetic screening panels 17 . Over one hundred unique, low frequency, germline TMEM127 variants have been reported in the context of familial or sporadic PHEOs, PGLs and/or RCCs 4,7-10, [12][13][14][18][19][20][21][22][23][24][25][26][27] . However, many of these TMEM127 variants, especially missense changes, are currently classified as variants of uncertain significance (VUS).…”

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Functional characterization of germline variants in theTMEM127tumor suppressor reveals novel insights into its membrane topology and trafficking

Flores¹,

Deng²,

Cheng³

et al. 2020

Preprint

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Purpose: To better understand the function of the transmembrane protein TMEM127, a poorly known tumor suppressor gene associated with pheochromocytomas, paragangliomas and renal carcinomas, we evaluated patient-derived germline variants.Methods: Subcellular localization and steady-state levels of 21 tumor-associated, transiently expressed TMEM127 variants were compared to the wild-type protein using immunofluorescence and immunoblot analysis, respectively, in cells genetically modified to lack endogenous TMEM127. Membrane topology and endocytic mechanisms were also assessed. Results:We identified three subgroups of mutations and determined that 15 of the 21 variants (71%), including 9 of 15 missense variants (60%), are pathogenic or likely pathogenic, through loss of membrane binding ability, stability and/or internalization capability. Investigation into an N-terminal cluster of missense variants uncovered a previously unrecognized transmembrane domain, indicating that TMEM127 is a four-, not a three-, transmembrane domain-containing protein. Additionally, a C-terminal variant with predominant plasma membrane localization revealed an atypical, extended acidic, dileucine-based motif required for TMEM127 internalization through clathrinmediated endocytosis. Conclusion:We characterized the functional deficits of several germline TMEM127 variants and identified novel structure-function features of TMEM127, namely, a fourth transmembrane domain and an endocytic motif. These findings will assist in TMEM127 variant interpretation and will help guide future studies investigating the cellular role of TMEM127.1

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