Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
By J. Toro, M. Nickerson, M. Wei, M. Warren, G. Glenn, M. Turner, Laveta M. Stewart, P. Duray, Ousman Tourre, N. Sharma and 7 more. American Journal of Human Genetics, 2003
606 citations recorded by the source corpus.
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder characterized by smooth-muscle tumors of the skin and uterus and/or renal cancer. Although the identification of germline mutations in the fumarate hydratase (FH) gene in European families supports it as the susceptibility gene for HLRCC, its role in families in North America has not been studied. We screened for germline mutations in FH in 35 families with cutaneous leiomyomas. Sequence analysis revealed mutations in FH in 31 families (89%). Twenty different mutations in FH were identified, of which 18 were novel. Of these 20 mutations, 2 were insertions, 5 were small deletions that caused frameshifts leading to premature truncation of the protein, and 13 were missense mutations. Eleven unrelated families shared a common mutation: R190H. Eighty-one individuals (47 women and 34 men) had cutaneous leiomyomas. Ninety-eight percent (46/47) of women with cutaneous leiomyomas also had uterine leiomyomas. Eighty-nine percent (41/46) of women with cutaneous and uterine leiomyomas had a total hysterectomy, 44% at age < or =30 years. We identified 13 individuals in 5 families with unilateral and solitary renal tumors. Seven individuals from four families had papillary type II renal cell carcinoma, and another individual from one of these families had collecting duct carcinoma of the kidney. The present study shows that mutations in FH are associated with HLRCC in North America. HLRCC is associated with clinically significant uterine fibroids and aggressive renal tumors. The present study also expands the histologic spectrum of renal tumors and FH mutations associated with HLRCC.
Subfields: Molecular Biology, Physiology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/c5de0b299204a00628221fc9d4115519ab4da93f
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Citations in the corpus
- HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. (2005, background): “Information pertaining to germline FH status of these HLRCC patients has been previously reported (Toro et al., 2003; Wei et al., 2005).”
- Mitochondrial tumour suppressors: a genetic and biochemical update (2005, background): “In particular, no specific type of mutation seems to be associated with the development of renal-cell cancer”
- The genetic basis of kidney cancer: a metabolic disease (2010, background): “Germline mutations of the FH gene have been detected in over 90% of North American individuals with HLRCC”