Nearly all hereditary paragangliomas in the Netherlands are caused by two founder mutations in the SDHD gene

Hereditary paragangliomas or glomus tumors are usually benign slow-growing rumors in the head and neck region. The inheritance pattern of hereditary p araganglioma is autosomal dominant with imprinting. Recently, we have ident ified the SDHD gene encoding subunit D of the mitochondrial respiratory cha in complex II as one of the genes involved in hereditary paragangliomas. He re, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertai ned Dutch paraganglioma families, respectively. These two mutations were al so detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor f or the hereditary nature of the disorder in isolated patients. in addition, we demonstrate that the maternally derived wild-type SDHD allele is lost i n tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene. (C) 2001 Wiley-Liss, Inc.