{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:59:11Z","timestamp":1760151551909,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,28]],"date-time":"2022-03-28T00:00:00Z","timestamp":1648425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wayne State University Start-up fund","award":["253452"],"award-info":[{"award-number":["253452"]}]},{"name":"National Nature Science Foundation of China","award":["81671514"],"award-info":[{"award-number":["81671514"]}]},{"name":"Outstanding Young and Middle-Aged Technology Innovation Team Project of Hubei Provincial Department of Education","award":["T2020003"],"award-info":[{"award-number":["T2020003"]}]},{"name":"the youth talent support program of Hubei Province","award":["3345642"],"award-info":[{"award-number":["3345642"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Von Hippel-Lindau (VHL) genes are intimately involved in renal cell carcinoma (RCC), including clear cell RCC (ccRCC) pathogenesis. However, the contribution of pathogenic VHL mutations to ccRCC remains poorly understood. We report a xanthoderm with non-obstructive azoospermia (NOA)-associated cystic ccRCC, and the missense VHL mutation (c.262T &gt; C, p.Try88Arg). In a 34-year-old patient, a urologic physical examination identified hard epididymis, and imaging tests revealed deferens-associated NOA, as well as multi-organ hydatid cysts, including bilateral epididymal cysts, bilateral testicular cysts, bilateral renal cysts, and pancreatic cysts. Five years later, ccRCC was developed based on clinical and radiologic evidence. Two different prediction models of protein structure and multiple sequence alignment across species were applied to assess the pathological effects of the VHL mutation. The reliability of the assessment in silico was determined by both the cellular location and protein levels of the mutant products, using IF and Western blot, respectively. Our study shows that the missense VHL mutation (c.262T &gt; C, p.Try88Arg) plays a deleterious role in pVHL functions, as predicted by multiple sequence alignment across species. While a structural analysis identified no significant structural alterations in pVHL, the detrimental effects of this mutation were determined by exogenous expression, evidenced by a markedly different spatial distribution and reduced expression of mutant pVHL. This is the first report of the VHL gene mutation (c.475T &gt; C, p.Try88Arg) in a xanthoderm.<\/jats:p>","DOI":"10.3390\/curroncol29040192","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:40:14Z","timestamp":1648590014000},"page":"2376-2384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Whole-Exome Sequencing Identifies the VHL Mutation (c.262T &gt; C, p.Try88Arg) in Non-Obstructive Azoospermia-Associated Cystic Renal Cell Carcinoma"],"prefix":"10.3390","volume":"29","author":[{"given":"Yonghong","family":"Man","sequence":"first","affiliation":[{"name":"Department of Occupational Health and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuejun","family":"Shang","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical School of Nanjing University Affiliated Jinling Hospital, Nanjing 210002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, Medical School of Nanjing University Affiliated Jinling Hospital, Nanjing 210002, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Occupational Health and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan 430065, China"},{"name":"Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suheng","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Occupational Health and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Shiang","sequence":"additional","affiliation":[{"name":"Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, WI 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Occupational Health and Environmental Medicine, School of Public Health, Wuhan University of Science and Technology, Wuhan 430065, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhibing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, Wayne State University, Detroit, MI 48210, USA"},{"name":"Department of Obstetrics & Gynecology, The C.S. Mott Center for Human Growth and Development, Detroit, MI 48201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1159\/000447180","article-title":"Physical Activity Decreases Kidney Cancer Mortality","volume":"10","author":"Liss","year":"2017","journal-title":"Curr. Urol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"100","DOI":"10.21037\/atm.2016.01.31","article-title":"Combination therapy for metastatic renal cell carcinoma","volume":"4","author":"Buonerba","year":"2016","journal-title":"Ann. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cancer Genome Atlas Research Network (2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499, 43\u201349.","DOI":"10.1038\/nature12222"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1056\/NEJMoa1505917","article-title":"Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma","volume":"374","author":"Linehan","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.ccr.2014.07.014","article-title":"The somatic genomic landscape of chromophobe renal cell carcinoma","volume":"26","author":"Davis","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.3233\/KCA-170008","article-title":"Molecular Classification of Renal Cell Carcinoma and Its Implication in Future Clinical Practice","volume":"1","author":"Casuscelli","year":"2017","journal-title":"Kidney Cancer"},{"key":"ref_7","first-page":"1","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1093\/ajcp\/aqaa176","article-title":"BAP1-Mutated Clear Cell Renal Cell Carcinoma","volume":"155","author":"Gallan","year":"2021","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1586\/14737159.2015.1068122","article-title":"BAP1, PBRM1 and SETD2 in clear-cell renal cell carcinoma: Molecular diagnostics and possible targets for personalized therapies","volume":"15","author":"Piva","year":"2015","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_10","first-page":"877","article-title":"Phenotypic drug screening and target validation for improved personalized therapy reveal the complexity of phenotype-genotype correlations in clear cell renal cell carcinoma","volume":"32","author":"Schneider","year":"2014","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1159\/000453198","article-title":"The Clinicopathological Significance of Epigenetic Silencing of VHL Promoter and Renal Cell Carcinoma: A Meta-Analysis","volume":"40","author":"Yang","year":"2016","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.15586\/jkcvhl.2015.41","article-title":"Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma","volume":"2","author":"Ashouri","year":"2015","journal-title":"J. Kidney Cancer VHL"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1007\/s12094-010-0485-9","article-title":"Von Hippel-Lindau syndrome: Molecular mechanisms of the disease","volume":"12","author":"Calzada","year":"2010","journal-title":"Clin. Transl. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.semcancer.2012.06.001","article-title":"The VHL\/HIF axis in clear cell renal carcinoma","volume":"23","author":"Shen","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"799886","DOI":"10.3389\/fgene.2021.799886","article-title":"Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100922","DOI":"10.1016\/j.eucr.2019.100922","article-title":"Obstructive azoospermia secondary to bilateral epididymal cystadenomas in a patient with von Hippel-Lindau","volume":"27","author":"Gomella","year":"2019","journal-title":"Urol. Case Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20","DOI":"10.15586\/jkcvhl.2017.88","article-title":"A Review of Von Hippel-Lindau Syndrome","volume":"4","author":"Varshney","year":"2017","journal-title":"J. Kidney Cancer VHL"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/his.13749","article-title":"Clear cell renal cell carcinoma with wild-type von Hippel-Lindau gene: A non-existent or new tumour entity?","volume":"74","author":"Batavia","year":"2019","journal-title":"Histopathology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1148\/rg.2018184005","article-title":"Tumors in von Hippel-Lindau Syndrome: From Head to Toe-Comprehensive State-of-the-Art Review","volume":"38","author":"Ganeshan","year":"2018","journal-title":"Radiographics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00418-008-0416-9","article-title":"Structure and function of mammalian cilia","volume":"129","author":"Satir","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.ajhg.2016.06.022","article-title":"Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility","volume":"99","author":"Thomas","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4131","DOI":"10.1242\/dev.02595","article-title":"The roles of cilia in developmental disorders and disease","volume":"133","author":"Bisgrove","year":"2006","journal-title":"Development"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"600","DOI":"10.2174\/1871527314666150429113851","article-title":"Characterization of cancer stem cells and primary cilia in medulloblastoma","volume":"14","author":"Gate","year":"2015","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Adamiok-Ostrowska, A., and Piekie\u0142ko-Witkowska, A. (2020). Ciliary Genes in Renal Cystic Diseases. Cells, 9.","DOI":"10.3390\/cells9040907"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1111\/j.1582-4934.2010.01238.x","article-title":"Two sides to every story: The HIF-dependent and HIF-independent functions of pVHL","volume":"15","author":"Li","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"305","DOI":"10.4149\/neo_2014_039","article-title":"Primary cilia in gastrointestinal stromal tumors","volume":"61","author":"Dvorak","year":"2014","journal-title":"Neoplasma"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1681\/ASN.2012050490","article-title":"Loss of the ciliary kinase Nek8 causes left-right asymmetry defects","volume":"24","author":"Manning","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2177","DOI":"10.1093\/hmg\/ddt070","article-title":"Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression","volume":"22","author":"Frank","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1093\/hmg\/ddr544","article-title":"The Nek8 protein kinase, mutated in the human cystic kidney disease nephronophthisis, is both activated and degraded during ciliogenesis","volume":"21","author":"Zalli","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","first-page":"5320","article-title":"Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene","volume":"63","author":"Ma","year":"2003","journal-title":"Cancer Res."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/4\/192\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:44:40Z","timestamp":1760136280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/29\/4\/192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,28]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["curroncol29040192"],"URL":"https:\/\/doi.org\/10.3390\/curroncol29040192","relation":{},"ISSN":["1718-7729"],"issn-type":[{"type":"electronic","value":"1718-7729"}],"subject":[],"published":{"date-parts":[[2022,3,28]]}}}