title: Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata.
abstract: Multiple cutaneous and uterine leiomyomata syndrome (MCL) is an autosomal dominant disease characterized by the presence of concurrent benign tumors of smooth muscle origin (leiomyoma) in the skin and uterus of affected females, and in the skin of affected males. MCL can also be associated with type II papillary renal cell cancer (HLRCC). The genetic locus for MCL and HLRCC was recently mapped to chromosome 1q42.3-43 and subsequently, dominantly inherited mutations in the fumarate hydratase gene ( FH ) were identified. Importantly, analysis of the FH gene in tumors of MCL patients revealed a second mutation inactivating the wild-type allele in some tumors. Based on these findings, it has been suggested that FH may function as a tumor suppressor gene in MCL. Here, we report the analysis of the FH gene in a group of 11 MCL families, with the identification of 8 different mutations accounting for the disease in all families. One of the mutations, 905-1G>A, has been identified in 4 families of Iranian origin. The analysis of highly polymorphic markers in the vicinity of the FH gene showed a shared haplotype in these 4 families, suggesting that 905-1G>A represents a founder mutation. Collectively, identification of 5 novel and 3 recurrent mutations further supports the role of FH in the pathogenesis of MCL.
authors.affiliation: Department of Dermatology, Columbia University, New York, New York, USA.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Chuang
authors.forename: Amalia
authors.initials: A
authors.lastname: Martinez-Mir
authors.forename: Adam
authors.initials: A
authors.lastname: Geyer
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Engler
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.forename: Peter B
authors.initials: PB
authors.lastname: Cserhalmi-Friedman
authors.forename: Derek
authors.initials: D
authors.lastname: Gordon
authors.forename: Liran
authors.initials: L
authors.lastname: Horev
authors.forename: Barbara
authors.initials: B
authors.lastname: Lukash
authors.forename: Eric
authors.initials: E
authors.lastname: Herman
authors.forename: Manuel Prieto
authors.initials: MP
authors.lastname: Cid
authors.forename: Sarah
authors.initials: S
authors.lastname: Brenner
authors.forename: Marina
authors.initials: M
authors.lastname: Landau
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.forename: Maria Pilar
authors.initials: MP
authors.lastname: Garcia Muret
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.forename: Abraham
authors.initials: A
authors.lastname: Zlotogorski
mesh_terms: D005260:Female; D018703:Founder Effect; D005649:Fumarate Hydratase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007889:Leiomyoma / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D012878:Skin Neoplasms / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics*
chemical_list: D005649:Fumarate Hydratase