Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene

We have identified a family segregating von Hippel-Lindau (VHL) disease wit h a previously unreported T547A mutation in exon 1 of the VHL gene that cau ses a Tyr112 to Asn missense alteration in the protein. The mutation was id entified by nucleotide sequencing and confirmed by restriction enzyme diges tion. The mutation cosegregated with the disease in all five tested affecte d individuals from the extended family. The family consists of more than 10 0 at-risk individuals over seven generations. To date, we have identified 1 3 affected individuals of whom seven have had renal cell carcinoma and one has had a pheochromocytoma. No other case of a neuroendocrine tumor of the pancreas or adrenal gland (pheochromocytoma) was found or recognized retros pectively. Other manifestations in this family include retinal angioma and hemangioblastoma of the central nervous system. We also found the T547A mut ation in three asymptomatic members of the family, ages 12, 19, and 20, Ano ther mutation, T547C, which causes Tyr112 to His, has been seen at the same position and has been associated with VHL type 2A (pheochromocytoma, but n o renal cell carcinoma) in two families with a total of 22 affected individ uals [Chen F, Slife L, Kishida T, Mulvihill J, Tisherman SE, Zbar B, 1996: J Med Genet 33:716-717]. Thus, different amino acid changes at the same pos ition can cause very distinct clinical phenotypes, It will be interesting t o elucidate the functional differences that underlie the different phenotyp es. (C) 1999 Wiley-Liss, Inc.