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The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched- related gene, TRC8

1998; National Academy of Sciences; Volume: 95; Issue: 16 Linguagem: Inglês

10.1073/pnas.95.16.9572

1091-6490

Robert M. Gemmill, James West, Ferenc Boldog, Naotake Tanaka, Linda Robinson, Jeremy C. Smith, Frederick W. B. Li, Harry A. Drabkin,

Genetics and Neurodevelopmental Disorders

The 3;8 chromosomal translocation, t(3;8)(p14.2;q24.1), was described in a family with classical features of hereditary renal cell carcinoma. Previous studies demonstrated that the 3p14.2 breakpoint interrupts the fragile histidine triad gene ( FHIT) in its 5′ noncoding region. However, evidence that FHIT is causally related to renal or other malignancies is controversial. We now show that the 8q24.1 breakpoint region encodes a 664-aa multiple membrane spanning protein, TRC8, with similarity to the hereditary basal cell carcinoma/segment polarity gene, patched . This similarity involves two regions of patched , the putative sterol-sensing domain and the second extracellular loop that participates in the binding of sonic hedgehog. In the 3;8 translocation, TRC8 is fused to FHIT and is disrupted within the sterol-sensing domain. In contrast, the FHIT coding region is maintained and expressed. In a series of sporadic renal carcinomas, an acquired TRC8 mutation was identified. By analogy to patched , TRC8 might function as a signaling receptor and other pathway members, to be defined, are mutation candidates in malignant diseases involving the kidney and thyroid.