Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.
Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent...
| Asıl Yazarlar: | , , , , , , |
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| Materyal Türü: | Journal article |
| Dil: | English |
| Baskı/Yayın Bilgisi: |
2005
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| _version_ | 1826266671943254016 |
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| author | Alam, N Olpin, S Rowan, A Kelsell, D Leigh, I Tomlinson, I Weaver, T |
| author_facet | Alam, N Olpin, S Rowan, A Kelsell, D Leigh, I Tomlinson, I Weaver, T |
| author_sort | Alam, N |
| collection | OXFORD |
| description | Heterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding A-site, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development in MCUL. That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function. |
| first_indexed | 2024-03-06T20:42:29Z |
| format | Journal article |
| id | oxford-uuid:34bc17f6-c2e7-4653-95c6-d48ace63e5cf |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:42:29Z |
| publishDate | 2005 |
| record_format | dspace |
| spelling | oxford-uuid:34bc17f6-c2e7-4653-95c6-d48ace63e5cf2022-03-26T13:27:50ZMissense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:34bc17f6-c2e7-4653-95c6-d48ace63e5cfEnglishSymplectic Elements at Oxford2005Alam, NOlpin, SRowan, AKelsell, DLeigh, ITomlinson, IWeaver, THeterozygous germline mutations in fumarate hydratase (FH) predispose to the multiple cutaneous and uterine leiomyomatosis syndrome (MCUL), which, when co-existing with renal cancer, is also known as hereditary leiomyomatosis and renal cell cancer. Twenty-seven distinct missense mutations represent 68% of FH mutations reported in MCUL. Here we show that FH missense mutations significantly occurred in fully conserved residues and in residues functioning in the FH A-site, B-site, or subunit-interacting region. Of 24 distinct missense mutations, 13 (54%) occurred in the substrate-binding A-site, 4 (17%) in the substrate-binding B-site, and 7 (29%) in the subunit-interacting region. Clustering of missense mutations suggested the presence of possible mutational hotspots. FH functional assay of lymphoblastoid cell lines from 23 individuals with heterozygous FH missense mutations showed that A-site mutants had significantly less residual activity than B-site mutants, supporting data from Escherichia coli that the A-site is the main catalytic site. Missense FH mutations predisposing to renal cancer had no unusual features, and identical mutations were found in families without renal cancer, suggesting a role for genetic or environmental factors in renal cancer development in MCUL. That all missense FH mutations associating with MCUL/hereditary leiomyomatosis and renal cell cancer showed diminished FH enzymatic activity suggests that the tumor suppressor role of fumarate hydratase may relate to its enzymatic function. |
| spellingShingle | Alam, N Olpin, S Rowan, A Kelsell, D Leigh, I Tomlinson, I Weaver, T Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title | Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title_full | Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title_fullStr | Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title_full_unstemmed | Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title_short | Missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer. |
| title_sort | missense mutations in fumarate hydratase in multiple cutaneous and uterine leiomyomatosis and renal cell cancer |
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