GERMLINE MUTATIONS IN THE VON-HIPPEL-LINDAU DISEASE (VHL) GENE IN FAMILIES FROM NORTH-AMERICA, EUROPE, AND JAPAN

Germline mutation analysis was performed in 469 VHL families from Nort h America, Europe, and Japan. Germline mutations were identified in 30 0/469 (63%) of the families tested; 137 distinct intragenic germline m utations were detected. Most of the germline VHL mutations (124/137) o ccurred in 1-2 families; a few occured in four or more families, The c ommon germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg 167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possibl e to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were i dentified that produced three distinct cancer phenotypes: (1) renal ca rcinoma without pheochromocytoma, (2) renal carcinoma with pheochromoc ytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mut ations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype phenotype correl ations in VHL. (C) 1996 Wiley-Liss, Inc.(dagger)