Genetic analysis of von Hippel-Lindau disease.
Mutations in the von Hippel-Lindau (VHL) gene are responsible for VHL disease, congenital polycythemia, and are found in many sporadic tumor types as well. Reports of VHL mutations are dispersed throughout original articles and databases that have not been recently updated. We compiled a comprehensive mutation table of 1,548 germline and somatic VHL mutations, derived from this protein of only 213 amino acids. We describe detailed phenotype and gene mutation information for 945 VHL families, including 30 previously unpublished kindreds from The Netherlands (six novel mutations). These data represent the most extensive catalog of germline VHL mutations to date. We also review VHL disease, known and theorized pathogenesis of common VHL manifestations, and genotype-phenotype correlations. Analysis of all VHL families, excluding germline mutations resulting in congenital polycythemias, describes the spectrum of mutation types: 52% missense, 13% frameshift, 11% nonsense, 6% in-frame deletions/insertions, 11% large/complete deletions, and 7% splice mutations. This easy-to-use compilation of VHL mutations is intended to facilitate research and function as a necessary adjunct for physicians when providing patient information.
Department of Medical Oncology, University Medical Center Utrecht, Universiteitsweg 100, Utrecht, The Netherlands.
Morgan
M
Nordstrom-O'Brien
Rob B
RB
van der Luijt
Ellen
E
van Rooijen
Ans M
AM
van den Ouweland
Danielle F
DF
Majoor-Krakauer
Martijn P
MP
Lolkema
Aram
A
van Brussel
Emile E
EE
Voest
Rachel H
RH
Giles
D016368:Frameshift Mutation; D056726:Genetic Association Studies; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D006623:von Hippel-Lindau Disease / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology