Human Molecular Genetics, 2003, Vol. 12, No. 11 1241-1252
DOI: 10.1093/hmg/ddg148
© 2003 Oxford University Press
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency
1Molecular and Population Genetics Laboratory, 2Computational Genome Analysis Laboratory and 3Mathematics, Statistics and Epidemiology Department, Cancer Research UK, Lincoln's Inn Fields, London WC2A 3PX, UK, 4Department of Dermatopathology, St John's Institute of Dermatology, St Thomas's Hospital, London SE1 7EH, UK, 5Department of Histopathology, John Radcliffe Hospital, Oxford OX3 9PU, UK, 6Torbay Hospital, Devon TQ2 7AA, UK, 7Treliske Hospital, Truro, Cornwall TR1 3LJ, UK, 8Addenbrookes Hospital, Cambridge CB2 2QQ, UK, 9Warwickshire Hospital, Warwick CV3 5BW, UK, 10St Mary's Hospital, Portsmouth PO3 6AD, UK, 11Blackburn Royal Infirmary, Blackburn BB2 3LR, UK, 12Dewsbury District Hospital, West Yorkshire WF13 4JU, UK, 1388 Claylands Road, London SW8 1NJ, UK, 14West Suffolk Hospital, Bury St Edmunds IP33 2QZ, UK, 15Cannock Chase Hospital, Cannock WS11 2XY, UK, 167 Shilton Garth Close, Old Earswick, York YO3 9SQ, UK, 1714 Forest Gardens, Lyndhurst, Hampshire SO43 7AF, UK, 18Pontefract General Infirmary, West Yorkshire WF8 1PL, UK, 19Halifax General Hospital, West Yorkshire HX3 0PW, UK, 20North Hampshire Hospital, Basingstoke, Hampshire RG24 9NA, UK, 21Leeds General Infirmary, Leeds LS1 3EX, UK, 22Dermatologia H.U. Virgin Macarena Avda Dr Fedriani, No. 3 Sevilla 41071, Spain, 23Department of Dermatology, Warsaw School of Medicine, Koszykowa 82a, Warsaw 02-008, Poland, 24Stoke Mandeville Hospital, Buckinghamshire HP21 8AL, UK, 25Independent Hospital, Tunbridge Wells TN3 0RD, UK, 26Princess Margaret Hospital, Swindon SN1 4JU, UK, 27BUPA Hospital, Harpenden AL5 4BP, UK, 28Service Dermatologique CHR Brest Avenue, Foch-Brest 29200, France, 29Wrexham Maelor Hospital, Wrexham LL13 7TD, UK, 30Doncaster Royal Infirmary, South Yorkshire DN2 5LT, UK, 31James Cook University Hospital, Middlesborough TS4 3BW, UK, 32Department of Medical Genetics, Belfast City Hospital, Belfast BT9 7AB, UK, 33Molecular and Cellular Pathology, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, UK, 34Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, UK, 35Centre for Cutaneous Research, St Bartholomew's and London School of Medicine and Dentistry, Queen Mary and Westfield College, Whitechapel, London E1 2AT, UK and 36Neonatal Screening and Chemical Pathology, Sheffield Children's Hospital, Sheffield S10 2TH, UK
Received February 12, 2003; Accepted April 4, 2003
Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.
* To whom correspondence should be addressed.
The authors wish it to be known that, in their opinion, the first four authors should be regarded as joint First Authors.
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