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

Abstract

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.

Genetic analysis of von Hippel-Lindau disease

“…Initially it was noted that phenotypes in Caucasian VHL families paralleled Japanese families for most mutations . Later studies by Yoshida et al [2000] found that mutations p.Arg113Ter, p.Gln132Ter, p.Leu158Val, and p.Cys162Tyr, which were previously associated with VHL Type 1 in Western cultures [Crossey et al, 1994a;Glavac et al, 1996;Maher et al, 1996;Zbar et al, 1996], were associated with VHL Type 2 in Japanese families [Clinical Research Group for VHL in Japan, 1995;Yoshida et al, 2000]. A study of 15 Korean patients showed the majority of VHL Type 1 mutations were nonmissense mutations, similar to those found in Japan and Western cultures [Cho et al, 2009].…”

“…Some genotype-phenotype correlations for VHL disease have been established, but can be perplexing [Friedrich, 2001] mutations [Brauch et al, 1999;Chen et al, 1995;Crossey et al, 1994b;Glavac et al, 1996;Maher et al, 1996;Zbar et al, 1996]. Our analysis of all VHL families found 52% had missense, 13% had frameshift, 11% had nonsense, 6% had in-frame deletions/ insertions, 11% had large/complete deletions, and 7% had splice mutations (Tables 2-4, Fig.…”

“…Generally speaking, germline VHL missense mutations confer a high risk for the development of pheochromocytomas, whereas loss of pVHL through large deletions or nonsense-mediated decay appears to be incompatible with pheochromocytoma development Crossey et al, 1994b;Cybulski et al, 2002;Glavac et al, 1996;Hes et al, 2000aHes et al, , 2000bMaher et al, 1996;Neumann and Bender, 1998;Ong et al, 2007;Zbar et al, 1996]. Interestingly, missense mutations causing amino acid changes on the surface of pVHL appear to have a higher risk for pheochromocytomas than missense mutations occurring deep within the protein; surface missense mutations also appear to have a higher risk for pheochromocytomas than deletions, nonsense, and frameshift mutations [Ong et al, 2007].…”

“…We compiled a mutation table of germline and somatic VHL mutations, but focused primarily on germline mutations (Supp. [Brauch et al, 1995;Chen et al, 1995;Glavac et al, 1996;Stolle et al, 1998]. …”

A family with hydrocephalus as a complication of cerebellar hemangioblastoma: identification of Pro157Leu mutation in the VHL gene

“…Heterogeneity of phenotypes is a salient feature of VHL syndrome, and the disease has been classified into at least two clinical entities: VHL type 1 does not include pheochromocytomas in its phenotype, and VHL type 2 does Glavac et al 1996). In spite of the variety of manifestations within both categories, the clinical courses of VHL patients are usually chronic in nature.…”