Intronic mutation of the VHL gene associated with central nervous system hemangioblastomas in two Chinese families with Von Hippel-Lindau disease: case report.

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.

A novel mutation in the VHL gene in a Chinese family with von Hippel-Lindau disease.

BACKGROUND: Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer syndrome, and VHL is identified as a tumor suppressor gene. The main objective of this study was to identify disease-causing mutations in a Chinese family affected with VHL disease. METHODS: Genomic DNA was extracted from peripheral blood from a Chinese family with VHL. A predicted pathogenic variant was identified by targeted exome capture technology and next-generation sequencing. RESULTS: A novel heterozygous mutation (c.349 T > A, p.W117R) was detected in affected family members. No mutation was detected in unaffected family members or in the 150 normal controls. The mutation segregated with the disease phenotype throughout three generations. Histopathological examination revealed the characteristics of hemangioblastoma. CONCLUSIONS: A novel W117R was detected in the VHL gene that caused retinal hemangioblastomas in affected members of a Chinese family.

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an inherited tumor syndrome caused by germline mutations in the VHL tumor suppressor gene. It is characterized by hemangioblastoma in the central nervous system and retina, renal cell carcinoma, pancreatic tumor and cysts, and pheochromocytoma. In this study, we detected 26 germline mutations in the VHL gene of Korean patients, of which 1 was a novel mutation, c.417_418insT. We also integrated our data from this study with the published literature to identify 55 VHL germline mutations in Koreans, and identified a unique hotspot at codon 70. Nine unrelated patients (9/55, 16.4%) had the same amino-acid substitution at codon 70 (Glu70Lys) and showed VHL type 1 phenotypes. Although this mutation was shown to have a mild effect on VHL function, four of the nine patients (44.4%) subsequently developed multiple central nervous system hemangioblastomas or retinal hemangioblastoma. However, this hotspot has not been identified in Chinese or Japanese patients. This study provides information on the spectrum of VHL mutations in Korean VHL disease and contributes to a better understanding of VHL disease in terms of improvements in the clinical management of VHL families.

[Germ line mutations in Chinese kindreds with von Hippel-Lindau syndrome].

OBJECTIVE: To investigate the germ line mutations in Chinese kindreds with von Hippel-Lindau syndrome (VHL) and to explore its role in clinical management. METHODS: The clinical and familial data were reviewed from 6 Chinese kindreds with VHL, of which the VHL germ line mutation in 21 members was analysed by polymerase chain reaction and sequencing analysis. RESULTS: Among 6 kindreds, there were 5 type I and 1 type IIA. The germ line mutations consisted of 4 missense mutations, 1 nonsense mutation and 1 deletion, of which 4 mutations existed in exon 1, 1 in exon 2 and 1 in exon 3. Of the 21 members who volunteered for genetic analysis, 14 members presented the VHL germ line mutations, including 10 affected patients, 1 suspected patients and 3 carriers. CONCLUSION: The germ line mutations in Chinese kindreds with VHL could be dominant in exon 1. It plays an important role in early detection of asymptomatic patients and the carriers, in the diagnosis of VHL and the clinical screening for members in the VHL families.

Mutations in the VHL tumor suppressor gene and associated lesions in families with von Hippel-Lindau disease from central Europe.

von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome predisposing to retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma and pancreatic tumors. Clinically two types of the disease can be distinguished: VHL type 1 (without pheochromocytoma) and VHL type 2 (with pheochromocytoma). We report VHL germline mutations and trends in phenotypic variation in families from central Europe. We identified 28 mutations in 53/65 (81.5%) families with 18 (64%) mutations being unique to this population. Whereas types and distribution of mutations as well as a strong correlation of missense mutations with the VHL 2 phenotype were similar to those identified in other populations, these families have provided new insights into the molecular basis for variability in the VHL 2 phenotype. Seven different missense mutations in exons 1 and 3 varied in their biological consequences from a minimal VHL 2 phenotype with pheochromocytoma only to a full VHL 2 phenotype with RCC and pancreatic lesion. These findings contribute to a better understanding of the fundamental mechanisms of VHL disease and its phenotypic variability. Further, we have provided rapid VHL screening for the families in central Europe, which has resulted in improved diagnosis and clinical management.

Germline mutations in the von Hippel-Lindau disease (VHL) gene in Japanese VHL. Clinical Research Group for VHL in Japan.

The von Hippel-Lindau disease (VHL) gene is a putative tumor suppressor gene responsible for VHL, an autosomal dominantly inherited multitumor syndrome. It is also implicated in the development of sporadic tumors including clear cell renal carcinoma and central nervous system hemangioblastoma. To define the molecular basis of VHL patients in Japanese populations, we tested for germline mutations of the VHL gene in 45 unrelated Japanese VHL patients by single-strand conformation polymorphism (SSCP) analysis and Southern blot analysis. We detected 23 (51%) intragenic mutations and three (6.7%) deletions by SSCP analysis and Southern blot respectively. The intragenic mutations consisted of 14 missense mutations, seven microdeletions or insertions and two splice-site mutations. Interestingly, nine of 10 mutations in exon 1 are localized in a short region of 37 nucleotides. Five unique sites of mutation were included, which were not seen in previous studies. Unlike Western VHL patients, nonsense mutations were not found in Japanese VHL patients. If the presence of pheochromocytomas is regarded as phenotypic marker for VHl classification, the mutations found in 22 VHL patients without pheochromocytoma consisted of 11 missense mutations, six microdeletions or insertions, two splice-site alterations and three deletions. The mutations found in four VHL patients with pheochromocytomas consisted of one missense mutation at nucleotide 683 (codon 228), two missense mutations at nucleotide 712 (codon 238) and a novel 20 bp insertion at nucleotide 776 (codon 259). Although the mutations at codon 238 are the mutational hot spot found in Western VHL patients with pheochromocytomas, a 20 bp insertion of original VHL cDNA sequence, from nucleotide 777 to 796, is a unique mutation. Our results suggest that mutations in Japanese VHL patients contain some unique features compared with those in Western patients. VHL gene has a critical role for the etiology in VHL in Japanese populations as well as Western VHL.