Characterization of the human homologue of the mouse Tg737 candidate polycystic kidney disease gene

Abstract

We previously identified a gene from the mutant locus in a new mouse mutation that causes recessive polycystic kidney disease. Here we describe the cloning, characterization and mapping of the homologous human gene. The human and mouse genes are 95% identical at the predicted amino acid sequence level, and both genes encode a putative protein that contains a tetratricopeptide repeat motif. The human gene, called hTg737, is expressed with a broad tissue distribution that includes the the kidney and liver, and gives rise to a 2.9 kb mRNA. The gene contains 26 exons and spans a genomic region greater than 100 kb. Chromosome mapping experiments revealed that the hTg737 gene maps near the centromere on the long arm of human chromosome 13, at position 13q12.1. While this gene does not map to the primary locus that has been identified for ARPKD in humans, it may represent a candidate gene for other recessive renal disorders that have yet to be mapped.

The tetratricopeptide repeat containing Tg737 gene is a liver neoplasia tumor suppressor gene

“…DNA was isolated and analysed from the cell lines as described above. PCR analysis of the human Tg737 gene was performed as described previously (Schrick et al, 1995). Normal and tumorous liver DNA was kindly provided by Dr Randy Jirtle, Duke University.…”

“…The Tg737 gene was originally identi®ed by insertional mutagenesis and positional cloning as the gene which is altered in autosomal recessive polycystic kidney disease in the TgN737Rpw transgenic mouse line developed in the laboratory of Dr Richard Woychik at Oak Ridge National Laboratories (Moyer et al, 1994;Schrick et al, 1995;Richards et al, 1996Richards et al, , 1997. The Tg737 gene encodes a 824 amino acid protein which contains 10 tetratricopeptide repeat sequences, a protein motif found in multiple genes including several which function to control cellular proliferation and sporulation in the ®ssion yeast Schizosaccharomyces pombe Goeble and Yanagida, 1991;Hirano et al, 1990;Kumada et al, 1995;Moyer et al, 1994;Schrick et al, 1995;Sikorski et al, 1993).…”

“…The Tg737 gene encodes a 824 amino acid protein which contains 10 tetratricopeptide repeat sequences, a protein motif found in multiple genes including several which function to control cellular proliferation and sporulation in the ®ssion yeast Schizosaccharomyces pombe Goeble and Yanagida, 1991;Hirano et al, 1990;Kumada et al, 1995;Moyer et al, 1994;Schrick et al, 1995;Sikorski et al, 1993). In the initial description of the polycystic kidney disease associated with Tg737 gene mutation, additional organ alterations were observed including biliary dysplasia in the liver, an observation which was interpreted as liver stem cell (oval cell) hyperplasia (Moyer et al, 1994;Richards et al, 1996Richards et al, , 1997Schrick et al, 1995). This observation prompted us to investigate the role of the Tg737 gene in neoplasia of the liver since aberrant cellular proliferation is believed to play an important role in neoplasia (Cohen and Ellwein, 1990;Hennings et al, 1993;Sell and Pierce, 1994).…”

Structure and expression of Tg737, a putative tumor suppressor gene, in human hepatocellular carcinomas

“…To analyze the complete human Tg737 cDNA sequence, 20 we amplified four overlapping cDNA fragments using four primer sets (PR1/PR2; PR3/PR4; PR5/PR6; PR7/PR8) designed from the published nucleotide sequence of the human Tg737 cDNA 20 (Table 1).…”

“…17 The Tg737 gene is an ubiquitously expressed gene that encodes an 824-amino acid protein containing 10 copies of a 34-amino acid tetratricopeptide repeat motif. [18][19][20][21][22][23][24] Mutant mice lacking both Tg737 alleles show polycystic kidney disease and biliary liver cell proliferation. 25 In the liver of these mice, loss of the Tg737 product indeed results in the proliferation of a biliary epithelial cell population with characteristics similar to those described for oval cells.…”