Emergence of Talanin protein associated with human uric acid nephrolithiasis in the Hominidae lineage
Introduction
Uric acid nephrolithiasis (UAN) is a common multifactorial disorder characterized by the presence of small crystals and stones in the urinary tract when the urine becomes overly concentrated with uric acid (Jaeger, 1996, Curhan et al., 1997). Uric acid is produced during the metabolism of purines and, in most mammals, is further degraded by the hepatic enzyme, urate oxidase (uricase), to allantoin, which is excreted in the urine. Mutations in the uricase gene in human and great apes during the Miocene epoch determined the enzyme activity disappearance (Wu et al., 1992). As a consequence, in these species, the uric acid is the end product of purine metabolism and there is an increase of its serum level: (>2 mg/dl compared with most mammals <2 mg/dl). In the past, urate was considered an inert product without any physiological value, but the observation that urate oxidase activity was inactivated by several independent mutations was interpreted as evidence of an evolutionary advantage in elevated uric acid levels (Christen et al., 1970, Wacker, 1970). Because uric acid is a powerful antioxidant that directly scavenges reactive oxygen species and chelates iron, it played an important role in protecting hominoids from oxidative damage (Ames et al., 1981, Whiteman and Halliwell, 1996). In contrast, there is evidence that hyperuricemia is commonly associated with the risk of hypertension, of cardiovascular and renal diseases (Selby et al., 1990, Jossa et al., 1994, Wu et al., 1994, Cannon et al., 1966, Alderman et al., 1999, Verdecchia et al., 2000, Johnson et al., 2003). A likely evolutionary scenario posits that a urate homeostasis system developed against an excessive and detrimental hyperuricemia that was originally advantageous. However, selective evolutionary advantages resulting from the loss of uricase and disadvantages resulting from excessive accumulation of serum uric acid levels are probably related. The identification of human genes involved in uric acid nephrolithiasis may disclose pathways of uric acid metabolism.
Recently, in a study of UAN in an ancient founder Sardinian micropopulation, we identified a novel gene (ZNF365) encoding four different protein isoforms, one of which (Talanin) is associated with the disease (OMIM 605990) (Gianfrancesco et al., 2003). In this paper, we carried out an evolutionary analysis of ZNF365 gene. In mouse, we isolated the ortholog of ZNF365A, not involved in UAN, while the transcript ZNF365D encoding the Talanin protein is not found in mouse and rat. We detected it in New and Old World monkeys as a nonfunctional gene and found its expression in hominoids. The identification of this gene and its particular evolution offers the occasion to explore the emergence of a human gene and its specific function.
Section snippets
Isolation of cDNA clones
Mouse ZNF365A-related cDNA was obtained from a mix of mouse polyA+ RNA including lung, colon, retina, and brain, by RT-PCR using primer pairs based on the mouse EST sequences. Sequence databases were searched using the BLAST sequence alignment program (Altschul et al., 1990). We designed primers in order to yield a series of overlapping fragments spanning the entire cDNA. The cDNAs were subcloned into TOPO cloning vector (Invitrogen) and analyzed by Dye-Terminator cycle sequencing on ABI Prism
Isolation of mouse homologous of human ZNF365A
In order to isolate the murine ortholog of the four different transcripts and proteins generated by alternative splicing of the human ZNF365 gene, we performed an expressed sequence tag (EST) database search to identify ESTs of mouse-related genes. A variety of mouse ESTs were detected only for ZNF365A transcript, but no sequences with significant homology to ZNF365B, ZNF365C, and ZNF365D transcripts either at nucleotide or at protein level were found. By RT-PCR using primer pairs based on
Discussion
Searching for mouse orthologs of a recently isolated human gene, associated with uric acid nephrolithiasis, we detected an interesting differential evolutionary pattern. The human gene produces through alternative splicing four different transcripts: ZNF365A, ZNF365B, ZNF365C, and ZNF365D coding for different protein isoforms. We found that ZNF365A has a high homology with a mouse-related gene (Znf365A) while ZNF365B, ZNF365C, and ZNF365D are absent in rodents. Human, mouse, and rat genomic
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Present address: Institute of Food Science, CNR, Avellino, Italy.