Three novel VHL germline mutations in Korean patients with von Hippel-Lindau disease and pheochromocytomas

2005 ◽  
Author(s):  
Hio Kang ◽  
Il-Jin Kim ◽  
Jae-Hyun Park ◽  
Yong Shin ◽  
Sang-Geun Jang ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Von Hippel Lindau ◽  
Korean Patients ◽  
Von Hippel Lindau Disease

Germline mutations in the von Hippel–Lindau disease (VHL) gene in mainland Chinese families

2008 ◽  
Vol 134 (11) ◽  
pp. 1211-1218 ◽  
Author(s):  
Jin Zhang ◽  
Yiran Huang ◽  
Jiahua Pan ◽  
Dongming Liu ◽  
Lixin Zhou ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Chinese Families ◽  
Mainland Chinese ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease

Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease

2020 ◽  
Vol 243 ◽  
pp. 1-6
Author(s):  
Muhammad Faiyaz-Ul-Haque ◽  
Masood Jamil ◽  
Muhammad Aslam ◽  
Halah Abalkhail ◽  
Fouad Al-Dayel ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Vhl Gene ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease

scholarly journals Germline mutations in theVHLgene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family

2016 ◽  
Vol 17 (6) ◽  
pp. 599-603 ◽  
Author(s):  
Ping Yuan ◽  
Qipeng Sun ◽  
Hao Liang ◽  
Wenjun Wang ◽  
Ling Li ◽  
...  
Keyword(s):  
Germline Mutations ◽  
Von Hippel Lindau ◽  
Renal Lesions ◽  
Von Hippel Lindau Disease ◽  
Disease Family

A Comprehensive Study of the VHL-R200W Chuvash Polycythemia Mutation Reveals a Gradual Dysregulation of the Hypoxia Pathway in Oncogenesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4020-4020 ◽  
Author(s):  
Betty Gardie ◽  
Sophie Couvé ◽  
Charline Ladroue ◽  
Elodie Laine ◽  
Karène Mahtouk ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Development ◽  
Germline Mutations ◽  
Von Hippel Lindau ◽  
Functional Studies ◽  
Core Haplotype ◽  
Von Hippel Lindau Disease ◽  
Heterozygous Carriers ◽  
First Time ◽  
Comprehensive Study

Abstract Context : Germline mutations in genes involved in the hypoxia sensing pathway (VHL, PHD2/EGLN1, HIF2A/EPAS1) predispose patients to erythrocytosis associated with normal or high serum erythropoietin level. The more frequent mutation, VHL-R200W (R200W), has been identified in homozygous carriers with a congenital erythrocytosis named Chuvash polycythemia. Survival in the Chuvash patients was found to be reduced compared to control groups due to higher rates of arterial and venous thromboses, and to haemorrhagic events. Noteworthily, a characteristic of these patients and their parents, heterozygous for the mutation, is the total absence of tumor development as the opposite of heterozygous carriers of other VHL mutations. Indeed, VHL is a tumor suppressor gene and heterozygous carriers of VHLmutations have von Hippel-Lindau disease and are at high risk of multiple tumors (e.g. CNS hemangioblastomas, pheochromocytoma, renal cell carcinoma). The absence of tumor development in patients with congenital erythrocytosis remained unexplained. The R200W mutation is transmitted within a 340-kilobases haplotype inherited 14,000 to 62,000 years ago from a single founder event. The absence of tumor development in patients carrying the R200W mutation raised the possibility of the presence of a protective element within this core haplotype. Objective: The purpose of this study was to determine the mechanisms underlying the absence of tumor development in patients carrying the R200W mutation, healthy (heterozygous carriers) or with congenital erythrocytosis (homozygous). Methods: We report here one particular family carring a heterozygous R200W mutation associated, for the first time, with a typical von Hippel-Lindau disease (with pheochromocytoma, hemangioblastoma and renal cell carcinoma) (Olswang et al., 1998). We performed a comprehensive study with genotyping, phenotypic analysis, structural modeling, functional and transcriptomic studies of the R200W mutant in comparison to classical mutants involved in von Hippel-Lindau disease. For the first time, the use of inducible expression vectors encoding untagged VHL in the functional studies allowed the observation of very subtle effects. Results: We show that the R200W mutation alone is definitely not associated with the von Hippel Lindau disease because this particular family actually carries another pathogenic mutation, VHL-R161Q, on the same VHL allele, and the double mutated allele segregates with disease. Our genotyping showed that the doubled mutations lies on the Chuvash core haplotype transmitted with the R200W mutation. We can thus conclude that this haplotype does not contain any protective elements against cancer development and that the VHLmutations are, by themselves, predominantly responsible for manifestations of the von Hippel-Lindau disease. Functional studies demonstrate that the function of the R200W mutation is close to the wild type protein and the severity of disease manifestations observed in VHL syndrome is perfectly correlated with a gradient of pVHL dysfunction in hypoxia signaling pathways. Conclusion: We show that the R200W mutation associated with congenital erythrocytosis is at the bottom of an oncogenic gradient. These results validate for the first time in humans the recently proposed “continuum” model of tumor suppression, which differs from the classical Knudson’s two-hit model and implies that subtle gene dosage-sensitivity may underlie tumor predisposition. This model may be of major importance in our understanding of tumor risk in patients with erythrocytosis carrying germline mutations in other genes belonging the HIF pathway. Indeed, in rare cases, PHD2 and HIF2A pathogenic mutations also predispose patients to pheochromocytomas or paragangliomas development. Disclosures No relevant conflicts of interest to declare.

scholarly journals Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma

2007 ◽  
Vol 14 (2) ◽  
pp. 453-462 ◽  
Author(s):  
Esther Korpershoek ◽  
Bart-Jeroen Petri ◽  
Francien H van Nederveen ◽  
Winand N M Dinjens ◽  
Albert A Verhofstad ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Mutation Analysis ◽  
Somatic Mutations ◽  
Germline Mutations ◽  
Von Hippel Lindau ◽  
Adrenal Pheochromocytoma ◽  
Von Hippel Lindau Disease ◽  
Testing Algorithms ◽  
Succinate Dehydrogenase Subunit B ◽  
Testing Algorithm

Pheochromocytomas (PCCs) are rare tumors that arise from chromaffin tissue in the adrenal medulla, but can also occur in the abdomen outside the adrenals and are then called sympathetic paragangliomas (sPGLs). According to the literature, between 15 and 25% of apparently sporadic adrenal PCC and sPGL are caused by germline mutations in RET, von Hippel–Lindau disease (VHL), succinate dehydrogenase subunit B (SDHB), or subunit D SDHD. However, few studies have addressed the mutationfrequency of these candidate genes in selected subgroups of PCC andsPGL, such as bilateral adrenal PCC or extra-adrenal sPGL, and none have looked at somatic mutations by analyzing tumor tissue. Therefore, we have investigated the occurrence of germline and somatic mutations in RET, VHL, SDHB, and SDHD in comparatively large series of bilateral adrenal PCC (n = 33 patients) and sPGL (n = 26 patients), with the aim of determining the mutation frequency of each of these genes and to establish a genetic testing algorithm. Twenty-one RET, two VHL germline, and one SDHD mutations were found in the patients with bilateral adrenal PCC. In sPGL, one novel SDHB germline and one novel SDHB somatic mutation were observed. In addition, two SDHD germline mutations were found. We conclude that germline RET mutations are predominantly found in bilateral PCC, and that somatic and germline SDHB and SDHD mutations usually occur in sPGL, which has practical consequences for genetic testing algorithms. We suggest that sequential mutation analysis should be directed first at RET, followed by VHL and SDHD for patients with bilateral adrenal PCC at diagnosis, and at SDHB and SDHD for patients with sPGL.

Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene

1998 ◽  
Vol 12 (6) ◽  
pp. 417-423 ◽  
Author(s):  
Catherine Stolle ◽  
Gladys Glenn ◽  
Berton Zbar ◽  
Jeffrey S. Humphrey ◽  
Peter Choyke ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Germline Mutations ◽  
Suppressor Gene ◽  
Von Hippel Lindau ◽  
Von Hippel Lindau Disease ◽  
Disease Tumor Suppressor Gene

scholarly journals Functioning Thoracic Paraganglioma: Association with Von Hippel-Lindau Syndrome*

1997 ◽  
Vol 82 (10) ◽  
pp. 3356-3360
Author(s):  
Bernhard U. Bender ◽  
Carsten Altehöfer ◽  
Andrzej Januszewicz ◽  
Roland Gärtner ◽  
Heinrich Schmidt ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germline Mutations ◽  
Von Hippel Lindau ◽  
Men 2 ◽  
Associated Lesions ◽  
Adrenal Pheochromocytoma ◽  
Von Hippel Lindau Disease ◽  
Von Hippel Lindau Syndrome

Abstract Functioning thoracic paraganglioma (pheochromocytoma) is unusual and therefore suggestive of a pathogenesis distinct from that of sporadic adrenal pheochromocytoma. To determine whether the pheochromocytoma-associated syndromes Von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 2 (MEN 2) play a role in the development of thoracic functioning paragangliomas, germline DNA from five unselected patients with this rare tumor was analyzed for mutations in the genes that predispose to VHL and MEN 2. Genetic investigations and further clinical data revealed that three had VHL, with two different germline mutations of the vhl gene, but no individual was affected by MEN 2. Two of the three patients with VHL did not show any additional VHL-associated lesions. This result suggests that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, as such a diagnosis carries further important implications for the patient and family. Conversely, in patients suspected of a catecholamine-secreting tumor and known VHL, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected.

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