Dataset Information

Case report: a synonymous VHL mutation (c.414A?>?G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

ABSTRACT: BACKGROUND:von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL 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. CASE PRESENTATION:We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A?>?G (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's 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 VHL were established from the family. Mutant fibroblasts downregulated full-length VHL 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. CONCLUSIONS:Our study shows that the synonymous VHL mutation c.414A?>?G can within 7?years 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 VHL mutation using patient-derived fibroblasts. The mutation c.414A?>?G 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.

SUBMITTER: Liu F

PROVIDER: S-EPMC7045488 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

Liu Fang F Calhoun Barbara B Alam Md Suhail MS Sun Miaomiao M Wang Xuechun X Zhang Chao C Haldar Kasturi K Lu Xin X

BMC medical genetics 20200227 1

<h4>Background</h4>von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL 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.<h4>Case presentation</h4>We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-yea ...[more]

PMID: 32106822

Similar Datasets

Project description:BackgroundHemangioblastomas are benign (World Health Organization Grade I), highly vascular neoplasms commonly associated with Von Hippel-Lindau (VHL) disease.[2] The VHL tumor-suppressor gene, located on chromosome 3, is implicated in sporadic cases and cases associated with VHL disease. Hemangioblastomas most commonly arise in the posterior fossa; however, they may also be found supratentorially or within the spinal cord.[3] Surgical intervention is indicated for symptomatic lesions with a goal of complete resection of the enhancing nodule.[1].Case descriptionWe demonstrate the case of a 69-year-old man with a history of multiple hemangioblastomas who had undergone two previous craniotomies and Gamma-Knife radiosurgery (Video https://drive.google.com/file/d/1lUwsb80NLmIW2Enp-DVdtM9_Oqbid3Ih/view?usp=sharing). He presented with progressive imbalance and diplopia and was found to have a new lesion within the suprasellar cistern. Digital subtraction angiography (DSA) and magnetic resonance imaging (MRI) characteristics were typical of hemangioblastoma. Surgery was determined to be indicated, with a goal of vision preservation. Preoperative embolization was not possible because preoperative DSA demonstrated vascular supply by only small perforators directly from the internal carotid artery. Hypopituitarism was identified preoperatively, although diabetes insipidus was not present. The patient underwent a right orbitozygomatic craniotomy and extradural anterior clinoidectomy for access. The tumor was noted to encapsulate the infundibulum, which necessitated its sacrifice. Postoperatively, the patient remained at his neurologic baseline. He had a positive triphasic diabetes insipidus response and was discharged home on maintenance desmopressin. Postoperative MRI demonstrated complete lesion resection.The patient gave informed consent for treatment and video recording. Institutional review board approval was deemed unnecessary.ConclusionThis video highlights a safe and effective surgical technique for suprasellar lesions as well as the complex anatomy observed through an orbitozygomatic approach.

Dataset Information

Case report: a synonymous VHL mutation (c.414A?>?G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

Publications

Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets