Intronic mutation of the VHL gene associated with central nervous system hemangioblastomas in two Chinese families with
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CASE REPORT
Open Access
Intronic mutation of the VHL gene associated with central nervous system hemangioblastomas in two Chinese families with Von Hippel–Lindau disease: case report Zhen Liu1, Jingcheng Zhou2, Liang Li1*† , Zhiqiang Yi1†, Runchun Lu1, Chunwei Li1 and Kan Gong2
Abstract Background: Central nervous system (CNS) hemangioblastomas are the most frequent cause of mortality in patients with Von Hippel–Lindau (VHL) disease, an autosomal dominant genetic disease resulting from germline mutations in the VHL tumor suppressor gene, with most mutations occurring in the exons. To date, there have been no reports of CNS hemangioblastoma cases related to pathogenic variants in intron 2 of VHL, which encodes a tumor suppressor protein (i.e., pVHL) that regulates hypoxia-inducible factor proteins. Case presentation: We report the presence of a base substitution of c.464-1G > C and c.464-2A > G in the intron 2 of VHL causing CNS hemangioblastomas in six patients with VHL from two Chinese families. The clinical information about the two pathogentic variants has been submitted to ClinVar database. The ClinVar accession for NM_ 000551.3(VHL):c.464-1G > C was SCV001371687. This finding may provide a new approach for diagnosing and researching VHL-associated hemangioblastomas. Conclusions: This is the first report of a pathogenic variant at intron 2 in VHL-associated hemangioblastomas. Gene sequencing showed that not only exonic but also intronic mutations can lead to the development of CNS hemangioblastomas. Keywords: Central nervous system, Hemangioblastoma, Von Hippel–Lindau, Intronic mutation, Case report
Background Von Hippel–Lindau (VHL) disease is an autosomal dominant genetic disease resulting from germline mutations in the VHL tumor suppressor gene on chromosome 3 (3p25–26) within a 10 kb region. This gene consists of two introns and three exons and encodes a tumor suppressor protein (i.e., pVHL) that regulates * Correspondence: [email protected] † Liang Li and Zhiqiang Yi contributed equally to this work. 1 Department of Neurosurgery, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing 100034, China Full list of author information is available at the end of the article
hypoxia-inducible factor (HIF) proteins [1–3]. The main manifestation of VHL disease in the central nervous system (CNS) is hemangioblastoma (HGB). Some studies have shown that partial deletions are associated with a high risk of developing a large number of CNS HGBs. However, most mutations occur in the exons [4]. To date, no cases of intron 2 of VHL associated with CNS HGBs have been reported. Here, we report the cases of six patients with VHL-associated HGBs from two Chinese families with two types of intronic pathogenic variant in VHL.
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original autho
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