NIH Research Festival
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal dominant condition characterized by the development of cutaneous and uterine leiomyomas. Affected individuals are at risk for type 2 papillary renal cell cancer, and metastases can arise from tumors that are less than 1 cm. HLRCC is caused by germline mutations in fumarate hydratase (FH), the tricarboxylic acid cycle enzyme that catalyzes the interconversion of fumarate and L-malate. The FH gene is found at position 43 of the long arm of chromosome 1 and exists in both cytoplasmic and mitochondrion isoforms differentiated by alternative translation start sites. In this study, we are designing a skin biopsy biochemical diagnostic tool to test for alterations in FH protein function in a cohort of patients who show clinical manifestations of HLRCC but were negative for FH mutations via CLIA-certified genetic testing. Using genetically defined controls derived from dermal fibroblasts and malate dehydrogenase enzyme activity and expression as a reference for normalization, we have quantified the spectrum of FH enzyme activity, mRNA and protein expression, and protein mobility. Preliminary findings indicated decreased FH activity and protein expression and electrophoretic mobility in several patient samples, while FH mRNA expression appeared normal. This information will be crucial for targeted evaluation of whole genome data in these individuals. Additionally, we plan to evaluate FH enzyme, gene, and protein dispositions in B-Lymphocytes.
Scientific Focus Area: Cancer Biology
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