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Original Research

Open Access

A rare variant in the MARVELD2 gene is associated with Chinesen samples with ovarian endometriosis

  • Qiu-Yan Wan1,2,3
  • Rong-Fang Liu1,3
  • Yang Zou3
  • Yong Luo3
  • Jiang-Yan Zhou3
  • Ying-Hui Deng4
  • Xin Zeng3
  • Guo-Dong Gao3
  • Ou-Ping Huang1,3,5,*,

1The College of Medicine, Nanchang University, 330006 Nanchang, Jiangxi, China

2Department of Gynecological Oncology, Jiangxi Cancer Hospital, 330029 Nanchang, Jiangxi, China

3Key Laboratory of Women’s Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal & Child Healthcare Hospital, 330006 Nanchang, Jiangxi, China

4Department of Pathology, Jiangxi Provincial Maternal & Child Healthcare Hospital, 330006 Nanchang, Jiangxi, China

5Department of Gynecology, Jiangxi Provincial Maternal & Child Healthcare Hospital, 330006 Nanchang, Jiangxi, China

DOI: 10.31083/j.ejgo4301012 Vol.43,Issue 1,February 2022 pp.42-47

Submitted: 10 September 2021 Accepted: 18 November 2021

Published: 15 February 2022

*Corresponding Author(s): Ou-Ping Huang E-mail:


Objectives: Endometriosis is a common gynecological disease affecting up to ~10% of women at reproductive age. Prior combined studies implied that MARVELD2 might be involved in the pathogenesis of certain malignancies. Here, 211 Han Chinese samples with ovarian endometriosis were analyzed for the presence of MARVELD2 mutations. Methods: We analyze the potential presence of MARVELD2 mutations by direct DNA sequencing. Results: A total of 7 variants, 5 missense and 2 synonymous variants, were identified in our 211 ovarian endometriosis samples with different frequencies. Among the 5 missense variant, a missense rare variant p.V198M (c.592G>>A), was identified in 10 out of our 211 samples (4.74%). This rare variant was identified with extremely low frequency in 766 control samples from 766 Chinese women without endometriosis (0.13%, 1/766) and control samples in the public databases. The evolutionary conservation analysis results suggested that the MARVELD2 rare variant lead to highly conserved amino acid substitutions among 14 vertebrate species from Human to Snake. Furthermore, both the SIFT and Polyphen-2 programs predicted this rare variant to be ‘disease causing’. However, we failed to observe any statistical significance between the MARVELD2 rare variant and the available clinical data. Conclusions: We identified a potential pathogenic rare variant in the MARVELD2 gene in Chinese samples with ovarian endometriosis, indicating the MARVELD2 rare variant might play an active role in the pathogenesis of endometriosis.


MARVELD2; Rare variant; Ovarian endometriosis; Han Chinese

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Qiu-Yan Wan,Rong-Fang Liu,Yang Zou,Yong Luo,Jiang-Yan Zhou,Ying-Hui Deng,Xin Zeng,Guo-Dong Gao,Ou-Ping Huang. A rare variant in the MARVELD2 gene is associated with Chinesen samples with ovarian endometriosis. European Journal of Gynaecological Oncology. 2022. 43(1);42-47.


[1] Gaetje R, Holtrich U, Engels K, Kissler S, Rody A, Karn T, et al. Differential expression of claudins in human endometrium and endometriosis. Gynecological Endocrinology. 2008; 24: 442–449.

[2] Sampson JA. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. American Journal of Pathology. 1927; 3: 93–110.

[3] Young VJ, Brown JK, Saunders PTK, Horne AW. The role of the peritoneum in the pathogenesis of endometriosis. Human Reproduction Update. 2013; 19: 558–569.

[4] Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. Journal of Clinical Investigation. 2013; 123: 4036–4049.

[5] Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita

S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. Journal of Cell Biology. 2005; 171: 939–945.


Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, et al. Tricellulin is a Tight-Junction Protein Necessary for Hearing. The American Journal of Human Genetics. 2006; 79: 1040–1051.


Chishti MS, Bhatti A, Tamim S, Lee K, McDonald M, Leal SM, et al. Splice-site mutations in the TRIC gene underlie autosomal recessive nonsyndromic hearing impairment in Pakistani families. Journal of Human Genetics. 2008; 53: 101–105.

[8] Zheng J, Meng W, Zhang C, Liu H, Yao J, Wang H, et al. New SNP variants of MARVELD2 (DFNB49) associated with non-syndromic hearing loss in Chinese population. Journal of Zhe-jiang University: Science B. 2019; 20: 164–169.

[9] Somorácz A, Korompay A, Törzsök P, Patonai A, Erdélyi-Belle B, Lotz G, et al. Tricellulin Expression and its Prognostic Significance in Primary Liver Carcinomas. Pathology Oncology Research. 2014; 20: 755–764.

[10] Kojima T, Sawada N. Regulation of tight junctions in human normal pancreatic duct epithelial cells and cancer cells. Annals of the New York Academy of Sciences. 2012; 1257: 85–92.

[11] Korompay A, Borka K, Lotz G, Somorácz A, Törzsök P, Erdélyi-Belle B, et al. Tricellulin expression in normal and neoplastic human pancreas. Histopathology. 2012; 60: E76–E86.

[12] Kyuno T, Kyuno D, Kohno T, Konno T, Kikuchi S, Arimoto C, et al. Tricellular tight junction protein LSR/angulin-1 contributes to the epithelial barrier and malignancy in human pancreatic cancer cell line. Histochemistry and Cell Biology. 2020; 153: 5–16.

[13] Xu Z, Zhang L, Yu Q, Zhang Y, Yan L, Chen Z. The estrogen-regulated lncRNA H19/miR-216a-5p axis alters stromal cell invasion and migration via ACTA2 in endometriosis. Molecular Human Reproduction. 2019; 25: 550–561.

[14] Choi YS, Park JH, Yoon JK, Yoon JS, Kim JS, Lee JH, et al. Potential roles of aquaporin 9 in the pathogenesis of endometriosis. Molecular Human Reproduction. 2019; 25: 373–384.

[15] Liu J, Wang Y, Chen P, Ma Y, Wang S, Tian Y, et al. AC002454.1 and CDK6 synergistically promote endometrial cell migration and invasion in endometriosis. Reproduction. 2019; 157: 535–543.

[16] Lac V, Verhoef L, Aguirre-Hernandez R, Nazeran TM, Tessier-Cloutier B, Praetorius T, et al. Iatrogenic endometriosis harbors somatic cancer-driver mutations. Human Reproduction. 2019; 34: 69–78.

[17] Zou Y, Zhou J, Guo J, Wang L, Luo Y, Zhang Z, et al. The presence of KRAS, PPP2R1a and ARID1a mutations in 101 Chinese samples with ovarian endometriosis. Mutation Research. 2018; 809: 1–5.

[18] Zou Y, Zhou JY, Wang F, Zhang ZY, Liu FY, Luo Y, et al. Analysis of CARD10 and CARD11 somatic mutations in patients with ovarian endometriosis. Oncology Letters. 2018; 16: 491–496.

[19] Cao B, Zeng Y, Wu F, Liu J, Shuang Z, Xu X, et al. Novel TR-ERF1 mutations in Chinese patients with ovarian endometriosis. Molecular Medicine Reports. 2018; 17: 5435–5439.

[20] Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, et al. Clonal expansion and diversifification of cancer-associated mutations in endometriosis and normal endometrium. Cell Reports. 2018, 24: 1777–1789.

[21] Zhang JX, Qin MB, Ye Z, Peng P, Li SM, Song Q, et al. Association of tricellulin expression with poor colorectal cancer prognosis and metastasis. Oncology Reports. 2020; 44: 2174–2184.

[22] Angioni S, D’Alterio MN, Coiana A, Anni F, Gessa S, Deiana

D. Genetic Characterization of Endometriosis Patients: Review of the Literature and a Prospective Cohort Study on a Mediter-ranean Population. International Journal of Molecular Sciences. 2020; 21: 1765.

[23] Deiana D, Gessa S, Anardu M, Daniilidis A, Nappi L, D’Alterio MN, et al. Genetics of endometriosis: a comprehensive review. Gynecological Endocrinology. 2019; 35: 553–558.

[24] Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM, et al. Cancer-Associated Mutations in Endometriosis without Cancer. New England Journal of Medicine. 2017; 376: 1835–1848.

[25] Li X, Zhang Y, Zhao L, Wang L, Wu Z, Mei Q, et al. Whole-exome sequencing of endometriosis identifies frequent alterations in genes involved in cell adhesion and chromatin-remodeling complexes. Human Molecular Genetics. 2014; 23: 6008–6021.

[26] Wang K, Li T, Xu C, Ding Y, Li W, Ding L. Claudin-7 downreg-ulation induces metastasis and invasion in colorectal cancer via the promotion of epithelial-mesenchymal transition. Biochemical and Biophysical Research Communications. 2019; 508: 797–804.

[27] Tamura K, Dudley J, Nei M, Kumar S. MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0. Molecular Biology and Evolution. 2007; 24: 1596–1599.

[28] Choi Y, Chan AP. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics. 2015; 31: 2745–2747.

[29] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nature Methods. 2010; 7: 248–249.

[30] Krug SM, Amasheh S, Richter JF, Milatz S, Günzel D, Westphal JK, et al. Tricellulin Forms a Barrier to Macromolecules in Tricellular Tight Junctions without Affecting Ion Permeability. Molecular Biology of the Cell. 2009; 20: 3713–3724.

[31] Raleigh DR, Marchiando AM, Zhang Y, Shen L, Sasaki H, Wang Y, et al. Tight junction-associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Molecular Biology of the Cell. 2010; 21: 1200–1213.

[32] Steinthorsdottir V, Thorleifsson G, Aradottir K, Feenstra B, Sigurdsson A, Stefansdottir L, et al. Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nature Communications. 2016; 7: 12350.

[33] Uimari O, Rahmioglu N, Nyholt DR, Vincent K, Missmer SA, Becker C, et al. Genome-wide genetic analyses high-light mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis. Human Reproduction. 2017; 32: 780–793.

[34] Nyholt DR, Low S, Anderson CA, Painter JN, Uno S, Morris AP, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nature Genetics. 2012; 44: 1355–1359.

[35] Rahmioglu N, Montgomery GW, Zondervan KT. Genetics of Endometriosis. Women’s Health. 2015; 11: 577–586.

[36] Sapkota Y, Vivo ID, Steinthorsdottir V, Fassbender A, Bowdler L, Buring JE, et al. Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry. Scientific Reports. 2017; 7: 11380.

[37] Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, et al. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. Journal of Clinical Investigation. 2013; 123: 4036–4049.

[38] Masuda R, Semba S, Mizuuchi E, Yanagihara K, Yokozaki H. Negative regulation of the tight junction protein tricellulin by snail-induced epithelial-mesenchymal transition in gastric carcinoma cells. Pathobiology. 2010; 77: 106–113.

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