LETTER TO JMG

Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer

M Pithukpakorn^1,2, M-H Wei^2,3, O Toure², P J Steinbach⁴, G M Glenn², B Zbar⁵, W M Linehan⁵, J R Toro²

¹ Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
² Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
³ Program of Division of Cancer Epidemiology and Genetics, SAIC-Frederick Inc, Frederick, Maryland, USA
⁴ Center for Molecular Modeling, Center for Information Technology, National Institutes of Health
⁵ Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health

Correspondence to:
Jorge R Toro
Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Boulevard, Executive Plaza South, Room 7012, Rockville, MD 20892-7231, USA; toroj{at}mail.nih.gov

Background: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus.

Objective: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes.

Methods: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations.

Results: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22).

Conclusions: FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at-risk family members.

Abbreviations: FH, fumarate hydratase; FHD, fumarate hydratase deficiency; HIF, hypoxia inducible factor; HLRCC, hereditary leiomyomatosis and renal cell cancer; HPH, HIF-prolyl hydroxylase; NCI, National Cancer Institute

Keywords: fumarate hydratase; fumarase; enzyme activity; cytosolic; mitochondrial; renal carcinoma; genodermatoses

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