Molecular Genetic Diagnosis of von Hippel‐Lindau Disease: Analysis of Five Japanese Families

We analyzed deoxyribonucleic acids from blood samples of five Japanese von Hippel‐Lindau (VHL) disease families (three familial cases, two new mutations) for the presence of VHL gene mutations by single‐strand conformational polymorphism analysis and direct sequencing. Four of the five families showed germ line mutations in VHL gene, comprising 2 missense mutations, 1 deletion, and 1 splice‐site mutation. Two families had VHL gene mutations at exon 1; 1 family at exon 3; and 1 family at the splice‐site adjacent to exon 3. Presymptomatic patients were accurately diagnosed by these methods. However, one family did not show a VHL gene mutation in the germ line but showed a somatic mutation at exon 2 in the hemangioblastoma tissue. The consequence of the somatic mutation was a microdeletion leading to a frameshift mutation. Our study is the first report of VHL gene analyses of Japanese VHL disease families, and suggests that not only germ line mutation, but also somatic mutation can lead to development of a tumor associated with the VHL disease.