Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.

摘要: Uterine leiomyomata (fibroids) are common and clinically important tumors, but little is known about their etiology pathogenesis. We previously mapped a gene that predisposes to multiple fibroids, cutaneous renal cell carcinoma chromosome 1q42.3-q43 (refs 4-6). Here we show, through combination of mapping critical recombinants, identifying individuals with germline mutations screening predicted transcripts, this encodes fumarate hydratase, an enzyme the tricarboxylic acid cycle. Leiomyomatosis-associated result in absent or truncated protein, substitutions deletions highly conserved amino acids. Activity hydratase reduced lymphoblastoid cells from leiomyomatosis. This acts as tumor suppressor familial leiomyomata, its measured activity very low tumors Mutations FH also occur recessive condition deficiency, some parents people susceptible leiomyomata. Thus, heterozygous homozygous compound mutants have different clinical phenotypes. Our results provide clues pathogenesis fibroids emphasize importance housekeeping mitochondrial proteins types tumor.