GERMLINE MUTATIONS IN THE VON HIPPEL-LINDAU DISEASE (VHL) GENE IN JAPANESE VHL

The von Hippel-Lindau disease (VHL) gene is a putative tumor suppresso r gene responsible for VHL, an autosomal dominantly inherited multitum or syndrome. It is also implicated in the development of sporadic tumo rs including clear cell renal carcinoma and central nervous system hem angioblastoma. To define the molecular basis of VHL patients in Japane se populations, we tested for germline mutations of the VHL gene in 45 unrelated Japanese VHL patients by single-strand conformation polymor phism (SSCP) analysis and Southern blot analysis. We detected 23 (51%) intragenic mutations and three (6.7%) deletions by SSCP analysis and Southern blot respectively. The intragenic mutations consisted of 14 m issense mutations, sever! microdeletions or insertions and two splice- site mutations. Interestingly, nine of 10 mutations in exon 1 are loca lized in a short region of 37 nucleotides. Five unique sites of mutati on were included, which were not seen in previous studies. Unlike West ern VHL patients, nonsense mutations were not found in Japanese VHL pa tients. If the presence of pheochromocytomas is regarded as a phenotyp ic marker for VHL classification, the mutations found in 22 VHL patien ts without pheochromocytoma consisted of 11 missense mutations, six mi crodeletions or insertions, two splice-site alterations and three dele tions. The mutations found in four VHL patients with pheochromocytomas consisted of one missense mutation at nucleotide 683 (codon 228), two missense mutations at nucleotide 712 (codon 238) and a novel 20 bp in sertion at nucleotide 776 (codon 259). Although the mutations in codon 238 are the mutational hot spot found in Western VHL patients with ph eochromocytomas, a 20 bp insertion of original VHL cDNA sequence, from nucleotide 777 to 796, is a unique mutation. Our results suggest that mutations in Japanese VHL patients contain some unique features compa red with those in Western patients. VHL gene has a critical role for t he etiology in VHL in Japanese populations as well as Western VHL.