It is a type of phakomatosis that results from a mutation. The germline mutations are essentially missense while somatic mutations include deletions, insertions and nonsense. To standardize the collection of these informations, facilitate the mutational analysis of the vhl gene and promote the genotypephenotype analysis, a software. Novel homozygous vhl mutation in exon 2 is associated with. Analysis of vhl gene alterations and their relationship to clinical. Mutations resulting in altered vhl proteins can lead to familial erythrocytosis, type 2 ecyt2. Bidirectional sequencing of the entire coding region and intronexon boundaries of the vhl. Vhl gene, erythrocytosis, mutation analysis, varies.
All analyses were run in duplicate, blinded to vhl mutation status, and with positive. The vhl status in 86 conventional renal cell carcinomas was determined by mutation. Software and database for the analysis of mutations in the vhl gene. Of these, fiftyeight were found to contain vhl mutations. Software and database for the analysis of mutations in the vhl gene article pdf available in nucleic acids research 241. Vhl gene mutations associated with this condition either prevent the production of any vhl. The following were the eligibility criteria for the clinical protocol. In sporadic renal cell carcinoma, vhl mutation or methylation has been. Most defects in the vhl gene are point mutations, which will not be detected by mlpa. Germline mutations in the new e1 cryptic exon of the vhl.
We used sequentially sequencing method and multiple ligationdependent probe amplification mlpa analysis. To standardize the collection of these informations, facilitate the mutational analysis of the vhl gene and promote the genotypephenotype analysis, a software package. Vhl mutation analysis is very sensitive but during followup 10 patients. The detection of vhl mutations not only contributes to an early and precise. The gene view histogram is a graphical view of mutations across vhl. Vhl is a tumor suppressor gene localized on chromosome 3p2526. A clinicopathologic study of 10 cases with molecular analysis of the vhl gene author links open overlay panel lucia anna muscarella a michele bisceglia b carlos a. Structural bioinformatics mutation analysis reveals. The main objective of this study was to identify diseasecausing mutations in a chinese family affected with vhl disease. This process is difficult to follow and understand as events in a multitude of different genes can lead to similar outcomes without apparent cause. We studied vhl gene mutation in 31 kidney tumors from france.
Vhl mutation analysis in patients with isolated central. Mutations in the gene that causes vhl disease the vhl gene are inherited in an autosomal dominant manner. The database of vhl mutations was developed using the universal mutation database tool 2628. Analysis of vhl gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma alison c. Testing for vhl mutation analysis was first available at our institution in 1998, sdhd analysis in 2000, and sdhb testing in 2001. Software and database for the analysis of mutations in the. It is therefore recommended to use this salsa mlpa probemix in combination with sequence analysis of vhl. These mutations are displayed at the amino acid level across the full length of the gene by default. To standardize the collection of these informations, facilitate the mutational. Pdf software and database for the analysis of mutations. Several studies of families harboring these germline vhl mutations have resulted in the discovery that a predominance of large deletion events with premature protein truncation or complete protein loss occurs in type 1 patients and missense mutations commonly occurs in type 2 patients. Analysis software applied biosystems and analyzed using mutation. It is characterized by visceral cysts and benign tumors with potential for subsequent malignant transformation. Structural bioinformatics mutation analysis reveals genotype.
To handle the flow of all known vhl mutations and study genotypephenotype relations, we adapted the universal mutation database software to this gene 2628. Numerous reports have indicated that chromosome 3p is frequently detected in lung cancer 3, 4 and several tumor suppressor genes, including vhl. Nonsense and frameshift mutations abrogate the function of the vhl protein pvhl, whereas missense mutations can have different effects. Lindau vhl disease, a clinically heterogeneous cancer syndrome. In silico vhl gene mutation analysis and prognosis of.
Software and database for the analysis of mutations in the vhl. Vhl gene mutations associated with this condition either prevent the production of any vhl protein or lead to the production of an abnormal version of the protein. Conclusions vhl e1 cryptic exon mutations contribute to 1. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the vhl. Genomic dna was extracted from peripheral blood from a chinese family with vhl. It contains all mutations localized in the coding region of the vhl gene. In many institutions there are likely to be a number of pheochromocytoma patients treated prior to 2000 who have never had germline mutation analysis for vhl. Diagnosis of suspected jak2negative vhl related erythrocytosis associated with lifelong sustained increased rbc mass, elevated rbc count, hemoglobin, or hematocrit vhle overview. Author summary cancer is generally caused by a series of mutations accumulating over time in a healthy tissue, which becomes reprogrammed to proliferate at the expense of the hosting organism. Vhl gene, erythrocytosis, mutation analysis, varies mayo. A short commentary on vhl gene mutation analysis of a. For clinical diagnosis of isolated cases of vhl, at least two haemangioblastomas or a single haemangioblastoma in association with a visceral manifestation are required.
To our knowledge we are the first to report detailed methylation analysis of cpg sites in vhl exons 1 and 2, and to compare data to vhl promoter methylation and exonic mutations. In our series of 202 pheochromocytomas and paragangliomas, 75 presented a germline mutation in one of the nf1, ret, vhl, tmem127 or sdhx genes and 17 carried a somatic mutation in vhl. The vhl protein pvhl is a multiadaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes. Analysis of all vhl families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types. Analysis of vhl gene alterations and their relationship to. More recently, vhl has also been shown to harbor mutations in mesothelioma and small cell lung carcinoma. About 70 % of clear cell renal cell carcinoma ccrcc have vhl mutations. Restrict the view to a region of the gene by dragging across the histogram to highlight the region of interest, or by using the sliders in the filters panel to the left. In univariate analysis, patients who had vhl mutations in their tumors had improved 2 year overall survival rates compared to those who did not. This means that having a mutation in only one copy of the vhl gene in each cell is enough to increase a persons risk of developing vhl.
It contains all mutations localized in the coding region of the vhl. Ecyt2 is a clinically heterogeneous disorder characterized by congenital erythrocytosis with. Characterization of vhl missense mutations in sporadic. Few studies were done in indian subcontinent, amidst a surge in clinical reports on vhl specific manifestations. Improved detection of germline mutations in korean vhl. To identify those missense mutations with functional consequences, we sequenced vhl in 256 sporadic ccrcc and identified 187 different vhl mutations. Primers were designed to amplify the entire cod ing sequence plus flanking splice sites of vhl using primer3 software and. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the vhl gene product, pvhl. Vhl gene mutations and their effects on hypoxia inducible. In addition, there are several reports of compound heterozygotes associated with congenital polycythemia, 3 in combination with vhl r200w mutation, and others employing different exon 3 vhl missense mutations. The syndrome is correlated with mutations of the gene vhl. To standardize the collection of these informations, facilitate the mutational analysis of the vhl gene and promote the genotypephenotype analysis, a software package along with a computerized database have been created. Integrative genomic analysis reveals somatic mutations in.