Fine Mapping of the Region Including Hypogonadism (hgn) Locus on Rat Chromosome 10

Abstract

ABSTRACT. The hypogonadic rat (hgn/hgn) shows male sterility, reduced female fertility, and renal hypoplasia, controlled by a single recessive gene located on rat chromosome 10. We developed a fine map around the hgn locus using 565 rat backcross progeny and a Rat/ Hamster radiation hybrid panel. The hgn locus was linked to Aldoc (aldolase c) and whn (winged helix of nude), and located in a 0.34-cM region between D10Rat30 and D10Rat68. The distance of the region was approximately 840-kb on rat physical map. Neither loci responsible for male sterility nor renal hypoplasia has been mapped on the homologous regions of mouse chromosome 11 and human chromosome 17. Identification of the gene responsible for the hgn mutation would provide important information on urogenital development. KEY WORDS: hypogonadism, linkage map, radiation hybrid map.J. Vet. Med. Sci. 66(9): 1151-1154, 2004 Male hypogonadic rats (hgn/hgn) show severe hypogonadism that inherited as an autosomal single recessive manner. The weight of an adult hgn/hgn testis is almost equal to that of a normal female ovary and about 1% that of a normal rat testis. These animals have small male reproductive accessory organs but no female reproductive organs [18]. Plasma testosterone is low and levels of gonadotropins are high, indicating that the cause of hypogonadism lies within the testis itself [5]. Testicular pathogenesis begins in the fetal period and progresses during postnatal testicular development [20]. Most germ cells degenerate in the testes before entering meiosis because of Sertoli cell dysfunction [13,17]. hgn/hgn males show not only hypogonadism but also bilateral hypoplastic kidney (HPK) [19]. The HPK of hgn/hgn rat contains only one-quarter the number of nephrons that are found in the normal kidney [12]. Therefore, the HPK causes chronic progressive renal failure [14]. The phenotypes of this disorder resemble those of oligomeganephronia, a congenital renal hypoplasia reported in humans [2], in respect of the reduced number of nephrons with hypertrophy of individual nephrons [12]. This combination of HPK and hypogonadism makes it possible to distinguish hgn/hgn females from phenotypically normal ones in the HGN strain [19]. hgn/hgn females identified by the presence of HPK have hypoplastic ovaries at birth, reduced reproductive performance, and early reproductive senescence [11]. Therefore, the female hgn/hgn rat is a congenital animal model of premature ovarian failure (POF) in women [9,11]. No other mutant animal showing a phenotype similar to that of the hgn/hgn rat has been reported. Therefore, the hgn/hgn rat would be a useful model for investigating the development of the mammalian reproductive and urinary organs. Our recent report revealed that the hgn locus was located in the region close to the D10Mit2 locus on rat chromosome 10 [15]; in the previous study we presented only a rough linkage map around the hgn locus, using 48 backcross progeny and 11 rat microsatellite markers. In the present study, we performed further linkage analysis us...

Duplicated insertion mutation in the microtubule-associated protein Spag5 (astrin/MAP126) and defective proliferation of immature Sertoli cells in rat hypogonadic (hgn/hgn) testes

“…To construct a fine linkage map around hgn locus, we genotyped the backcross progeny with a newly generated polymorphic markers (Table 1) using previously obtained genomic DNA (Suzuki et al 1999(Suzuki et al , 2004a. PCRs, separation of PCR products, and gel staining, and data analysis were done as previously described (Suzuki et al 2004a).…”

“…PCRs, separation of PCR products, and gel staining, and data analysis were done as previously described (Suzuki et al 2004a).…”

“…Rats were assumed to be C/C if, after mating with carriers, none of at least 11 pups was affected. PCR of genomic DNA and polyacrylamide gel electrophoresis were performed as described (Suzuki et al 2004a). The sequence of the Spag5 cDNA fragment containing the mutation site of the hgn allele was BLAST-searched against the rat genome (Map Viewer, National Center for Biotechnology Information (NCBI) http://www.ncbi.nlm.nih.gov/mapview/).…”

“…We previously reported that the hgn locus was linked to aldorase C (Aldoc) and located in an 840 kb region between D10Rat195 and D10Rat68 (Suzuki et al 2004a). This region includes an unsettled segment of rat chromosome 10, in which the order of loci is opposite to that reported in the homologous regions of mouse chromosome 11 and human chromosome 17.…”

“…All of these effects are controlled by a single recessive allele (hgn) located on chromosome 10 (Suzuki et al 1999(Suzuki et al , 2004a. In adult male hgn/hgn rats, the plasma testosterone level is low, the gonadotropin levels are high, and testis weight is about 1% the weight of a normal testis .…”