Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: An extended study of 77 families

We have previously reported on the analysis of germ-line mutations in Japan ese von Hippel-Lindau disease (VHL) patients and found mutations in 26 fami lies. We have now extended these studies to include an additional 41 VHL fa milies. Germ-line mutation of the VHL, gene was screened by DNA-SSCP, direc t sequencing, and Southern blot analysis, To summarize all of the data we h ave studied in this and our previous report, germ-line mutations have been detected in 55 of 77 (73%) (type 1: 41/62 (66%) and type 2: 14/15 (93%)) fa milies. We found similarities in the nature of germ-line mutations includin g mutational incidence, location, and DNA substitution patterns between Jap anese and Western VHL. These similarities mag reflect the predominance of e ndogenous mutational processes. We also found several interesting character istics in Japanese VHL. Twenty of 41 (49%) intragenic mutations were unique and not reported in the Western VHL, Four mutations (Arg113Stop, Gln132Sto p, Leu158Val, and Cys162Tyr) previously characterized as type 1 mutations w ere identified in the type 2 (with pheochromocytoma) Japanese families. Gen otype-phenotype correlation study suggested non-missense mutations predicte d to result in the loss of VHL function were associated with the occurrence of renal cell carcinoma, as in sporadic tumors, Our data add to the divers ity of VHL germ-line mutations and provide a better understanding of VHL di sease in terms of both clinical management and molecular pathogenesis.