{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:24:25Z","timestamp":1770888265501,"version":"3.50.1"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T00:00:00Z","timestamp":1582761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007544","name":"Boler Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007544","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008110","name":"Boler-Parseghian Center for Rare and Neglected Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008110","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201708340071"],"award-info":[{"award-number":["201708340071"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013290","name":"National Key Research and Development Program of China Stem Cell and Translational Research","doi-asserted-by":"crossref","award":["2017YFA0103902"],"award-info":[{"award-number":["2017YFA0103902"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genet"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of <jats:italic>VHL<\/jats:italic>. Pathogenic <jats:italic>VHL<\/jats:italic> mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Case presentation<\/jats:title>\n<jats:p>We report a Caucasian male with a family history of pheochromocytoma and the synonymous <jats:italic>VHL<\/jats:italic> mutation c.414A\u2009&gt;\u2009G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband\u2019s children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type <jats:italic>VHL<\/jats:italic> were established from the family. Mutant fibroblasts downregulated full-length <jats:italic>VHL<\/jats:italic> mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p>Our study shows that the synonymous <jats:italic>VHL<\/jats:italic> mutation c.414A\u2009&gt;\u2009G can within 7\u2009years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous <jats:italic>VHL<\/jats:italic> mutation using patient-derived fibroblasts. The mutation c.414A\u2009&gt;\u2009G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s12881-020-0976-7","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T11:03:33Z","timestamp":1582801413000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Case report: a synonymous VHL mutation (c.414A\u2009&gt;\u2009G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing"],"prefix":"10.1186","volume":"21","author":[{"given":"Fang","family":"Liu","sequence":"first","affiliation":[]},{"given":"Barbara","family":"Calhoun","sequence":"additional","affiliation":[]},{"given":"Md. Suhail","family":"Alam","sequence":"additional","affiliation":[]},{"given":"Miaomiao","family":"Sun","sequence":"additional","affiliation":[]},{"given":"Xuechun","family":"Wang","sequence":"additional","affiliation":[]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[]},{"given":"Kasturi","family":"Haldar","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0284-6478","authenticated-orcid":false,"given":"Xin","family":"Lu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2020,2,27]]},"reference":[{"issue":"9374","key":"976_CR1","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1016\/S0140-6736(03)13643-4","volume":"361","author":"RR Lonser","year":"2003","unstructured":"Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM. Oldfield EH: von Hippel-Lindau disease. Lancet. 2003;361(9374):2059\u201367.","journal-title":"Lancet"},{"key":"976_CR2","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1146\/annurev.pathol.2.010506.092049","volume":"2","author":"WG Kaelin","year":"2007","unstructured":"Kaelin WG. Von Hippel-Lindau disease. Annu Rev Pathol. 2007;2:145\u201373.","journal-title":"Annu Rev Pathol"},{"issue":"4","key":"976_CR3","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1007\/s40142-019-00180-9","volume":"7","author":"ER Maher","year":"2019","unstructured":"Maher ER. Sandford RN: von Hippel-Lindau disease: an update. Curr Genet Med Rep. 2019;7(4):227\u201335.","journal-title":"Curr Genet Med Rep"},{"issue":"3","key":"976_CR4","doi-asserted-by":"publisher","first-page":"20","DOI":"10.15586\/jkcvhl.2017.88","volume":"4","author":"N Varshney","year":"2017","unstructured":"Varshney N, Kebede AA, Owusu-Dapaah H, Lather J, Kaushik M, Bhullar JS. A review of Von Hippel-Lindau syndrome. J Kidney Cancer VHL. 2017;4(3):20\u20139.","journal-title":"J Kidney Cancer VHL"},{"issue":"12","key":"976_CR5","doi-asserted-by":"publisher","first-page":"2243","DOI":"10.1097\/IAE.0000000000002555","volume":"39","author":"ME Aronow","year":"2019","unstructured":"Aronow ME, Wiley HE, Gaudric A, Krivosic V, Gorin MB, Shields CL, Shields JA, Jonasch EW, Singh AD, Chew EY. VON HIPPEL-LINDAU DISEASE: Update on Pathogenesis and Systemic Aspects. Retina (Philadelphia, Pa). 2019;39(12):2243\u201353.","journal-title":"Retina (Philadelphia, Pa)"},{"issue":"283","key":"976_CR6","doi-asserted-by":"publisher","first-page":"1151","DOI":"10.1093\/qjmed\/77.2.1151","volume":"77","author":"ER Maher","year":"1990","unstructured":"Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990;77(283):1151\u201363.","journal-title":"Q J Med"},{"issue":"10","key":"976_CR7","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1136\/jnnp.55.10.898","volume":"55","author":"HPH Neumann","year":"1992","unstructured":"Neumann HPH, Schollmeyer P, Eggert HR, Scheremet R, Mohadjer M, Schumacher M, Wakhloo AK, Volk B, Hettmannsperger U, Riegler P, et al. Central nervous system lesions in von Hippel-Lindau syndrome. J Neurol Neurosurg Psychiatry. 1992;55(10):898\u2013901.","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"2","key":"976_CR8","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1111\/j.1582-4934.2010.01238.x","volume":"15","author":"M Li","year":"2011","unstructured":"Li M, Kim WY. Two sides to every story: the HIF-dependent and HIF-independent functions of pVHL. J Cell Mol Med. 2011;15(2):187\u201395.","journal-title":"J Cell Mol Med"},{"key":"976_CR9","doi-asserted-by":"publisher","unstructured":"Hu L, Xie H, Liu X, Potjewyd F, James LI, Wilkerson EM, Herring LE, Xie L, Chen X, Cabrera JC, et al. TBK1 is a synthetic lethal target in Cancer with VHL loss. Cancer Discov. 2019. https:\/\/doi.org\/10.1158\/2159-8290.CD-19-0837.","DOI":"10.1158\/2159-8290.CD-19-0837"},{"issue":"6399","key":"976_CR10","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1126\/science.aap8411","volume":"361","author":"J Zhang","year":"2018","unstructured":"Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, Liu XD, Jonasch E, Xie L, Chen X, et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science. 2018;361(6399):290\u20135.","journal-title":"Science"},{"issue":"6","key":"976_CR11","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1016\/j.cell.2014.01.051","volume":"156","author":"F Supek","year":"2014","unstructured":"Supek F, Mi\u00f1ana B, Valc\u00e1rcel J, Gabald\u00f3n T, Lehner B. Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014;156(6):1324\u201335.","journal-title":"Cell"},{"issue":"2","key":"976_CR12","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1038\/nrm.2016.139","volume":"18","author":"KS Manning","year":"2017","unstructured":"Manning KS, Cooper TA. The roles of RNA processing in translating genotype to phenotype. Nat Rev Mol Cell Biol. 2017;18(2):102\u201314.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"4","key":"976_CR13","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1002\/humu.23163","volume":"38","author":"T Soussi","year":"2017","unstructured":"Soussi T, Taschner PE, Samuels Y. Synonymous somatic variants in human Cancer are not infamous: a Plea for full disclosure in databases and publications. Hum Mutat. 2017;38(4):339\u201342.","journal-title":"Hum Mutat"},{"key":"976_CR14","doi-asserted-by":"crossref","unstructured":"Sharma Y, Miladi M, Dukare S, Boulay K, Caudron-Herger M, Gro\u00df M, Backofen R, Diederichs S. A pan-cancer analysis of synonymous mutations. Nat Commun. 2019;10(1):2569.","DOI":"10.1038\/s41467-019-10489-2"},{"issue":"15","key":"976_CR15","doi-asserted-by":"publisher","first-page":"8817","DOI":"10.1073\/pnas.95.15.8817","volume":"95","author":"A Schoenfeld","year":"1998","unstructured":"Schoenfeld A, Davidowitz EJ, Burk RD. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A. 1998;95(15):8817\u201322.","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"44","key":"976_CR16","doi-asserted-by":"publisher","first-page":"75989","DOI":"10.18632\/oncotarget.18376","volume":"8","author":"P Hascoet","year":"2017","unstructured":"Hascoet P, Chesnel F, Jouan F, Le Goff C, Couturier A, Darrigrand E, Mahe F, Rioux-Leclercq N, Le Goff X, Arlot-Bonnemains Y. The pVHL(172) isoform is not a tumor suppressor and up-regulates a subset of pro-tumorigenic genes including TGFB1 and MMP13. Oncotarget. 2017;8(44):75989\u20136002.","journal-title":"Oncotarget"},{"issue":"5","key":"976_CR17","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1182\/blood-2018-03-838235","volume":"132","author":"M Lenglet","year":"2018","unstructured":"Lenglet M, Robriquet F, Schwarz K, Camps C, Couturier A, Hoogewijs D, Buffet A, Knight SJL, Gad S, Couve S, et al. Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease. Blood. 2018;132(5):469\u201383.","journal-title":"Blood"},{"key":"976_CR18","doi-asserted-by":"crossref","unstructured":"Flores SK, Cheng Z, Jasper AM, Natori K, Okamoto T, Tanabe A, Gotoh K, Shibata H, Sakurai A, Nakai T, et al. A synonymous VHL variant in exon 2 confers susceptibility to familial pheochromocytoma and von Hippel-Lindau disease. J Clin Endocrinol Metab. 2019;104(9):3826\u201334.","DOI":"10.1210\/jc.2019-00235"},{"key":"976_CR19","doi-asserted-by":"crossref","unstructured":"Vangipuram M, Ting D, Kim S, Diaz R, Sch\u00fcle B. Skin punch biopsy explant culture for derivation of primary human fibroblasts. JoVE (J Vis Exp). 2013;(77):e3779.","DOI":"10.3791\/3779"},{"key":"976_CR20","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.3389\/fonc.2019.01037","volume":"9","author":"B Zhou","year":"2019","unstructured":"Zhou B, Wang J, Liu S, Peng X, Hong B, Zhou J, Ma K, Zhang J, Cai L, Gong K. Hemangioblastoma instead of renal cell carcinoma plays a major role in the unfavorable overall survival of Von Hippel-Lindau disease patients. Front Oncol. 2019;9:1037.","journal-title":"Front Oncol"},{"issue":"5112","key":"976_CR21","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1126\/science.8493574","volume":"260","author":"F Latif","year":"1993","unstructured":"Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993;260(5112):1317\u201320.","journal-title":"Science"},{"issue":"4","key":"976_CR22","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1007\/BF00279094","volume":"73","author":"H Neitzel","year":"1986","unstructured":"Neitzel H. A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet. 1986;73(4):320\u20136.","journal-title":"Hum Genet"},{"issue":"11","key":"976_CR23","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1007\/BF02619631","volume":"20","author":"MA Anderson","year":"1984","unstructured":"Anderson MA, Gusella JF. Use of cyclosporin a in establishing Epstein-Barr virus-transformed human lymphoblastoid cell lines. In vitro. 1984;20(11):856\u20138.","journal-title":"In vitro"},{"issue":"6743","key":"976_CR24","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/22780","volume":"400","author":"WC Hahn","year":"1999","unstructured":"Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. Nature. 1999;400(6743):464.","journal-title":"Nature"},{"issue":"9","key":"976_CR25","doi-asserted-by":"publisher","first-page":"1228","DOI":"10.1093\/neuonc\/nox034","volume":"19","author":"S Takayanagi","year":"2017","unstructured":"Takayanagi S, Mukasa A, Tanaka S, Nomura M, Omata M, Yanagisawa S, Yamamoto S, Ichimura K, Nakatomi H, Ueki K, et al. Differences in genetic and epigenetic alterations between von Hippel-Lindau disease-related and sporadic hemangioblastomas of the central nervous system. Neuro-Oncology. 2017;19(9):1228\u201336.","journal-title":"Neuro-Oncology"}],"container-title":["BMC Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12881-020-0976-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s12881-020-0976-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s12881-020-0976-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T00:28:01Z","timestamp":1614299281000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcmedgenet.biomedcentral.com\/articles\/10.1186\/s12881-020-0976-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,27]]},"references-count":25,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["976"],"URL":"https:\/\/doi.org\/10.1186\/s12881-020-0976-7","relation":{},"ISSN":["1471-2350"],"issn-type":[{"value":"1471-2350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,27]]},"assertion":[{"value":"18 July 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All procedures involving human subjects were approved by the Institutional Review Board at University of Notre Dame (Protocol# 17-10-4169). Written informed consent to participate was obtained from all of the participants in the study. Written informed consent to participate was obtained from the parents of the participants under the age of 16.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Written informed consent for publication of clinical details and clinical images was obtained from the all of the participants. Written informed consent for publication of clinical details and clinical images was obtained from the parents of any participant under the age of 18.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"42"}}