Mapping the Von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis.

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome in which affected individuals have a greatly increased predisposition to the development of haemangioblastomas of the central nervous system and retina, renal cell carcinoma and phaeochromocytoma. The VHL gene has been mapped to chromosome 3p25-p26 by genetic linkage studies and we have previously demonstrated that the VHL gene is tightly linked to the D3S601 locus (Zmax = 18.86 at theta = 0.0) suggesting that D3S601 maps close to the VHL disease gene. We have constructed a long range physical map around D3S601 and screened 91 VHL patients from 80 kindreds for germline rearrangements using pulsed field gel electrophoresis. Two patients showed abnormal fragments in Mlul digested DNA probed with D3S601. Further analysis was consistent with both patients having germline deletions (approximately 120 kb and 50 kb) telomeric to D3S601. These results have (i) established the position of the VHL disease gene with respect to D3S601, (ii) refined the localisation of the VHL disease gene to a small region (approximately 50 kb) of chromosome 3p25-p26 and (iii) excluded the plasma membrane Ca(+)+-transporting ATPase isoform 2 (PMCA-2) gene as a candidate gene for VHL disease.