Genotype-phenotype correlations in von Hippel-Lindau disease

Abstract

Communicated by David N. Cooper von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome resulting from mutations in the VHL tumor suppressor gene. VHL disease displays marked variation in expression and the presence of pheochromocytoma has been linked to missense VHL mutations. We analyzed genotype-phenotype correlations in 573 individuals with VHL disease. Routine clinical and radiological surveillance of VHL patients and at-risk relatives was associated with increased detection of retinal angiomatosis (73 vs. 59% of cases) and a reduction in age at diagnosis of renal cell carcinoma (RCC) (44.0710.9 vs. 39.7710.3 years). We confirmed the association of pheochromocytoma with missense mutations described previously, but stratifying missense mutations into those that resulted in substitution of a surface amino acid and those that disrupted structural integrity demonstrated that surface amino acid substitutions conferred a higher pheochromocytoma risk. Age at first manifestation of VHL disease was significantly earlier (P 5 0.001), and age-related risks of retinal angiomas and RCC were higher (P 5 0.022 and P 5 0.0008, respectively) in individuals with a nonsense or frameshift mutation than in those with deletions or missense mutations that disrupted the structural integrity of the VHL gene product (pVHL). These results extend genotype-phenotype-protein structure correlations in VHL disease and provide a baseline for future chemoprevention studies in VHL disease. Hum Mutat 28(2), 143-149, 2007.

Genetic analysis of von Hippel-Lindau disease

“…Some have found that VHL deletions extending to include the actin-regulator gene HSPC300 appear to lower the risk of RCC and retinal angiomas development [Franke et al, 2009;Maranchie et al, 2004]. Nonsense and frameshift mutations have a higher age-related risk for RCC and hemangioblastomas than missense mutations thought to interfere with pVHL's structural integrity [Ong et al, 2007]. Our analysis of pooled information also found nonsense and frameshift mutations occurring more in VHL Type 1 than VHL Type 2.…”

“…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].…”

“…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]. Thus, pheochromocytoma development appears to be related to an intact, but altered pVHL, which has seeded the hypothesis that these mutations may induce gain-of-function possibly through a dominant negative effect Lee et al, 2005;Maher and Kaelin, 1997;Stebbins et al, 1999].…”

Family history of von Hippel–Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients

“…In the previous reports, the genotype/phenotype relationship had been discussed, especially that of VHL germline mutations and pheochromocytoma. 16,21,26,27 Pheochromocytoma appeared in patients with missense mutations, and rarely happened in those with nonsense mutations and large deletions. 11,21 All of the 13 Chinese families with type 2 VHL disease carried missense mutations (Table 3).…”

von Hippel–Lindau disease: A clinical and scientific review

“…Although the risk of RCC varies in different subtypes of VHL disease (see below) in the most common forms (Types 1 and 2B) the lifetime risk is B70%. 1,24 Although the mean age at clinical diagnosis is B40 years, asymptomatic tumours are frequently detected earlier (though rarely below 16 years). [24][25][26] Histopathological examination of kidneys removed from VHL patients shows large numbers of microscopic tumour foci in apparently normal parenchyma that explain the high risk of multiple and bilateral RCC in VHL disease.…”