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ABSTRACT: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, noninsulin-dependent diabetes mellitus (NIDDM) in humans. NIDDM in this rat model was shown to be regulated by multiple genes. We have identified 14 quantitative trait loci (QTLs) responsible for NIDDM (Nidd1-14/of) on chromosomes 1, 5, 7, 8, 9, 11, 12, 14, 16, and 17 by a whole genome search in 160 F2 progenies obtained by mating the OLETF and the F344 rats. Among these loci, two QTLs, Nidd1 and 2/of, were declared significant loci at a genome-wide level. Nidd3, 8, 9, and 13/of exhibited heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between Nidd1/of and Nidd2/of, between Nidd1/of and Nidd10/of, between Nidd2/of and Nidd8/of, and between Nidd2/of and Nidd14/of. Furthermore, Nidd6 and 11/of showed linkage with body weight, and Nidd1, 2, 8, 9, 10, and 12/of had an interaction with body weight. These indicated that NIDDM in the OLETF would have a higher degree of genetic complexity. We suggest several interesting candidate genes located in rat genomic regions for Nidd1-14/of or the syntenic regions in human genome.
Experimental Diabetes Research 01/2012; 2012:582546. · 1.20 Impact Factor
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ABSTRACT: Obesity has been considered one of the leading causative agents for diseases such as type 2 diabetes, stroke, and heart attack. Due to their complex etiology, establishing auseful animal model is increasingly crucial for better molecular understanding of how obesity influences on disease development. OLETF rat is a spontaneous model of type 2 diabetes. We mapped 14 hyperglycemia QTLs in the genome of the OLETF rat and subsequently generated a panel of congenic strains each possessing OB-R mutation in F344 genetic background. Here we show that one of the loci, Nidd2/of, is highly responsive to obesity. When leptin receptor mutation is introgressed into the Nidd2/of congenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that the Nidd2/of locus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemia QTL Nidd1/of is additionally combined, the strain developed overt diabetes. A single QTL dissected out in spontaneous model normally exerts only mild effect on the quantitative trait, which makes it difficult to clone the gene. Our new model may help not only to identify the causative gene but also to investigate how obesity interacts with a QTL to regulate diabetic traits.
Experimental Diabetes Research 01/2012; 2012:858121. · 1.20 Impact Factor
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ABSTRACT: The condition of hyperglycemia results from multiple genetic and environmental factors. In recent years much progress has been made with regards to the search for candidate genes involved in the expression of various common diseases including type 2 diabetes. However less is known about the specific genetic and environmental connections that are important for the development of the disease. In the present study, we used hyperglycemic congenic rats to address this issue. When given a normal diet, two hyperglycemic QTLs (quantitative trait locus), Nidd2/of and Nidd10/of, showed mild obesity and/or increased blood glucose in the oral glucose tolerance test. In a double congenic strain possessing both loci, these indices were not significantly different from those of either single congenic strain. In contrast, the double congenic strain fed a high-calorie diet showed significantly greater body weight than the single congenic strains or normoglycemic control rats. Although postprandial glucose levels of the double congenic rat were not further aggravated even on the high fat diet, it was notable that the postprandial insulin levels were drastically elevated. From these results, we constructed a novel model animal especially for the study of prediabetic hyperinsulemia, in which two QTLs and an additional dietary condition are involved. This may help to shed light on the genetic basis and gene-to-diet interaction during the early stage of type 2 diabetes.
Experimental Animals 01/2011; 60(2):125-32. · 0.92 Impact Factor
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ABSTRACT: Marbling defined by the amount and distribution of intramuscular fat, so-called Shimofuri, is an economically important trait of beef cattle in Japan. Our previous study detected 3 single nucleotide polymorphisms (SNPs), g.231054C > T, g.3109537C > T and c.*188G > A, respectively, in the 5' flanking region of the titin (TTN), the 5' flanking region of the ribosomal protein L27a (RPL27A) and the 3' untranslated region of the akirin 2 genes (AKIRIN2), which have been considered as positional functional candidates for the genes responsible for marbling, and showed association of these SNPs with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the 3 SNPs among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Shorthorn, Holstein and Brown Swiss breeds.
We genotyped the TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A SNPs by polymerase chain reaction-restriction fragment length polymorphism method, using 101 sires and 1,705 paternal half sib progeny steers from 8 sires for Japanese Black, 86 sires and 27 paternal half sib progeny steers from 3 sires for Japanese Brown, 79 sires and 264 paternal half sib progeny steers from 14 sires for Japanese Shorthorn, 119 unrelated cows for Holstein, and 118 unrelated cows for Brown Swiss breeds. As compared to the frequencies of the g.231054C > T T, g.3109537C > T T and c.*188G > A A alleles, associated with high marbling, in Japanese Black breed that has been subjected to a strong selection for high marbling, those in the breeds, Japanese Shorthorn, Holstein and Brown Swiss breeds, that have not been selected for high marbling were null or lower. The Japanese Brown breed selected slightly for high marbling showed lower frequency than Japanese Black breed in the g.3109537C > T T allele, whereas no differences were detected between the 2 breeds in the frequencies of the g.231054C > T T and c.*188G > A A alleles.
Based on this finding, we hypothesized that the pressure of the strong selection for high marbling in Japanese Black breed has increased the frequencies of the T, T and A alleles at the TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A SNPs, respectively. This study, together with the previous association studies, suggested that the 3 SNPs may be useful for effective marker-assisted selection to increase the levels of marbling.
BMC Research Notes 01/2011; 4:10.
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Takahisa Yamada,
Seiki Sasaki,
Shin Sukegawa,
Takeshi Miyake,
Tatsuo Fujita, Hiroyuki Kose,
Mitsuo Morita,
Youichi Takahagi,
Hiroshi Murakami,
Fumiki Morimatsu,
Yoshiyuki Sasaki
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ABSTRACT: Marbling, defined by the amount and distribution of intramuscular fat, is an economically important trait of beef cattle in Japan. The c2-11#2 expressed sequence tag (EST) has been previously shown to possess expression difference in musculus longissimus muscle between low-marbled and high-marbled steer groups, and to be located within genomic region of a quantitative trait locus for marbling. Thus, the ribosomal protein L27a (RPL27A) gene containing the c2-11#2 EST sequence was considered as a positional candidate for the gene responsible for marbling. In the present study, a single nucleotide polymorphism (SNP) in the promoter region of the RPL27A, referred to as g.3109537C>T, was detected between the 2 steer groups. The SNP was associated with the predicted breeding value for beef marbling standard number by the analyses using Japanese Black beef cattle population. The effect of genotypes of the SNP on the predicted breeding value for subcutaneous fat thickness was not statistically significant. These findings suggest that the RPL27A SNP may be useful for effective marker-assisted selection to increase the levels of marbling in Japanese Black beef cattle.
Animal Science Journal 12/2009; 80(6):631-5. · 0.86 Impact Factor
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Takahisa Yamada,
Seiki Sasaki,
Shin Sukegawa,
Takeshi Miyake,
Tatsuo Fujita, Hiroyuki Kose,
Mitsuo Morita,
Youichi Takahagi,
Hiroshi Murakami,
Fumiki Morimatsu,
Yoshiyuki Sasaki
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ABSTRACT: Marbling, defined by the amount and distribution of intramuscular fat, is an economically important trait of beef cattle in Japan. The endothelial differentiation, sphingolipid G-protein-coupled receptor, 1 (EDG1) gene has been considered as a positional functional candidate for the gene responsible for marbling. We have recently reported that 2 single nucleotide polymorphisms (SNPs), c.-312A>G in the 5' untranslated region (UTR) and c.*446G>A in the 3' UTR in EDG1 were associated with marbling in Japanese Black beef cattle, but this was not functional and a causal mutation for marbling. In the present study, we detected 2 novel SNPs, referred to as g.1475435G>A and g.1471620G>T, in the 5' flanking region of the EDG1 between low-marbled and high-marbled steer groups, which were previously shown to have EDG1 expression differences in musculus longissimus muscle. The g.1475435G>A SNP seemed not to segregate in Japanese Black beef cattle. The g.1471620G>T SNP was associated with the predicted breeding value for beef marbling standard number by the analyses using Japanese Black beef cattle population. Based on these findings, we hypothesized that the g.1471620G>T SNP might have an impact on EDG1 expression and also marbling.
Animal Science Journal 08/2009; 80(4):486-9. · 0.86 Impact Factor
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ABSTRACT: Genetic bases of glomerulonephritis, a major cause of kidney dysfunction in humans and one of the most characteristic complications of autoimmune disorders such as Goodpasture syndrome, are complex. The Wistar-Kyoto (WKY) rat strain is well characterized for its susceptibility to autoantibodies against glomerular basement membrane (GBM), however the molecular mechanisms underlining the phenotype are largely unknown. Here we performed a whole genome scan using a backcross (BC) F(1) (WKY x DA) x WKY population, for which the DA rat is a nonsusceptible control strain. We found two significant QTLs on chromosomes 1 and 12, which were involved in elevated levels of proteinuria and kidney weight index, respectively. The relevance of these QTLs with the genetic factors involved in autoimmunity and renal disease is discussed.
Experimental Animals 05/2009; 58(2):193-8. · 0.92 Impact Factor
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ABSTRACT: The OLETF rat is a well-established model for the study of type 2 diabetes associated with obesity and has been shown to possess multiple hyperglycemic alleles in its genome. Here we focused on and carefully characterized one of the previously reported congenic strains, F.O-Nidd3/of that carries the OLETF allele of the Nidd3/of locus (also known as Niddm21 in the Rat Genome Database) in the normoglycemic F344 genetic background. A prominent finding was that the F1 progeny between the congenic and the F344 stain, whose genotype is heterozygote at the Nidd3/of locus, showed mild hyperglycemia equal to the parental congenic rat, suggesting that the OLETF allele is dominant. To our knowledge, this is the first study in which a diabetic QTL has been directly demonstrated to be dominant by using congenic strains.
Experimental Animals 05/2008; 57(2):135-8. · 0.92 Impact Factor
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ABSTRACT: Proteomic analysis was performed in an attempt to identify a gene responsible for the expression of type 2 diabetes using a congenic rat, F.O-Nidd2/of, which possesses a single hyperglycemic QTL locus derived from the diabetic OLETF (Otsuka Long-Evans Tokushima Fatty) rat. Since the genetic difference between the congenic and its host strain, the F344 rat, is limited to the introgressed segment of 38 cM or ca. 2% of the rat whole genome, any discordant protein spots on two dimensional polyacrylamid gel electrophoresis (2D PAGE) will be considered strong candidate genes of this locus. Here we analyzed ca. one thousand protein spots in three different tissue types, liver, muscle and pancreas at 10, 20 and 30 weeks of age, we found that an acidic protein of 55 kD in muscle tissue shifts towards acidic end in an age dependent fashion in the congenic strain. However, the shift was not observed in the control rat, which is intriguing because the timing of the shift corresponds to the age at which hyperglycemia begins in the congenic. Future biochemical analysis should aid in elucidating the molecular mechanisms of glucose metabolism.
The Journal of Medical Investigation 09/2007; 54(3-4):289-94.
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ABSTRACT: Glucose homeostasis is believed to be regulated by multiple genetic components, in addition to numerous external factors. It is therefore crucial to dissect and understand what roles each causative gene plays in maintaining proper glucose metabolism. In OLETF (Otsuka Long-Evans Tokushima Fatty) rat, a model of polygenic type 2 diabetes, at least 14 quantitative trait loci (QTLs) influencing plasma glucose levels were identified. In congenic strains some of the OLETF allelic variants were shown to increase glucose levels. In this study the focus was on two of the hyperglycemic loci, Nidd1/of and Nidd2/of. Congenic rats possessing OLETF genome fragment at either locus showed similar levels of mild hyperglycemia. A newly established double congenic rat showed a further aggravation of hyperglycemia. The Nidd1/of locus was also shown to function in the reduction of plasma leptin levels and fat weights, while the Nidd2/of locus led to increased plasma insulin and fat weights. Interestingly, both plasma leptin and fat weights reverted to the control levels in the double congenic rat. These results indicate that there is an epistatic interaction between the two loci. However, it is unlikely that the abnormal level of enhanced glucose homeostasis is mediated, at least not directly, by leptin or fat mass.
Mammalian Genome 09/2007; 18(8):609-15. · 2.89 Impact Factor
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ABSTRACT: The Long-Evans Cinnamon (LEC) rat has a spontaneous mutation, T helper immunodeficiency (thid), which causes a markedly reduced CD4(+) thymocyte population. Here we positionally clone the locus and identify a deletion in the gene encoding a receptor-like protein tyrosine phosphatase kappa (Ptprk) that led to complete loss of the transcript. The rat Ptprk gene exhibits 98% identity with the human and mouse counterparts and is expressed most abundantly in the CD4(-)CD8(-) double-negative stage. The downregulation of Ptprk in mouse immature thymocytes by RNA interference mimicked the thid phenotype. These results indicate that thid maps to the Ptprk locus and that functional Ptprk is crucial for lineage commitment or progression of CD4(+) T cells. We also found that Ptprk appears to function in parallel with or downstream of Th-POK/cKrox (also known as ZBTB7B), a master regulator of T cell lineage decision.
Genomics 07/2007; 89(6):673-7. · 3.02 Impact Factor
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ABSTRACT: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat exhibits polygenic obesity, and one of quantitative trait loci (QTLs) responsible for a susceptibility to obesity in the OLETF, Nidd6/of, has been mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 in (OLETF x normal) F2 intercross. In this study, we have attempted to identify the causal gene for the Nidd6/of QTL. A Nidd6/of congenic strain, constructed by introgressing the OLETF allele on the mapped Nidd6/of region in the normal F344 rat strain, confirmed the existence of the Nidd6/of as obesity QTL. The Nidd6/of region was refined to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using informative recombinants selected from (Nidd6/of congenic x F344) F1 x Nidd6/of congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, was regarded as the most prominent and physiologically relevant positional candidate for the Nidd6/of QTL. We found that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We further showed that the Nidd6/of QTL completely cosegregates with Pnlip VNTR in the informative recombinants from (Nidd6/of congenic x F344) F1 x Nidd6/of congenic backcross progenies. These results suggest that Pnlip is possible candidate for the Nidd6/of QTL.
Biochemical and Biophysical Research Communications 07/2005; 331(4):1270-6. · 2.48 Impact Factor
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ABSTRACT: Linkage analysis previously identified a hyperglycemic quantitative trait locus (QTL), Nidd 2/of, on rat Chromosome 14 in crosses utilizing OLETF (Otsuka Long Evans Tokushima Fatty) rat, a model for type 2 diabetes. A separate QTL study mapped an obesity QTL, Obs5, to the same chromosomal region. A congenic strain placing ca. 38 cM OLETF-derived segments containing both Nidd2/of and Obs5 on the F344 background was shown to possess mild diabetic and obese phenotypes, suggesting the presence of mutations affecting the glucose metabolism and fat accumulation. In order to localize the loci more precisely, we generated a series of deletion-subcongenic strains in which OLETF-segments were shortened from either ends. We found that there are at least two hyperglycemic QTLs within the Nidd2/of locus. We predict that they are localized towards both ends of the Nidd2/of region. In contrast, Obs5 QTL was further narrowed down to a single region of ca. 10 cM fragment.
The Journal of Medical Investigation 03/2005; 52(1-2):109-13.
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ABSTRACT: Leptin is produced by adipose tissue and acts as a feedback signal to the hypothalamus controlling energy homeostasis, by reducing food consumption and increasing energy expenditure. Because serum leptin levels are highly correlated with body fat mass, they can be used as an index to predict obesity-related diseases. However, the identity of genetic factors that influence the obesity and the obesity-related metabolic disorders remains largely unknown. In this study, we performed a whole-genome scan search, using 382 F2 intercross progeny between the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model for obese type 2 diabetes in human, and F344 rat, in order to identify loci responsible for the regulation of leptin and other obesity-related plasma substances. We have identified two quantitative trait loci (QTLs) contributing to serum leptin levels. These two loci, designated Olep1 [Chromosome (Chr) 2] and Olep2 (Chr 6), were homologous to those of human genome regions containing several potential candidate genes for obesity. These are fatty acid-binding protein 2 (FABP2), FABP4, and FABP5 for Olep1, and proopiomelanocortin (POMC) and glucose regulatory protein (GCKR) for Olep2.
Mammalian Genome 01/2004; 14(12):839-44. · 2.89 Impact Factor
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ABSTRACT: The rat strain Otsuka Long-Evans Tokushima Fatty (OLETF) is an animal model for type 2 diabetes mellitus. Nidd8/of has been identified as one of 14 quantitative trait loci (QTLs) involved in the diabetes by a whole genome search in 160 F2 progenies obtained by mating the OLETF and F344 rats. Comparative mapping between human and rat indicated that the Nidd8/of genomic region, near D9rat21 on rat chromosome 9, contains the calpain10 (Capn10) gene, which is putative type 2 diabetes-susceptibility gene in humans. In this study, we found no difference in Capn10 mRNA expression in the heart, liver, skeletal muscle and pancreas between OLETF and F344 rats at 5 and 10 weeks of age. However, we found a single nucleotide polymorphism (SNP) (A/A genotype in OLETF and G/G genotype in F344 and LETO rats) at the base 583 downstream from the translation start site in the rat Capn10 cDNA sequence. This SNP was deduced to substitute serine (OLETF) for glycine (F344 and LETO) at the 195 amino acid residue within the protease domain of rat Capn10. Because serine is generally not interchangeable with glycine in respect of the protein structure and function, it was deduced that the A/A genotype in OLETF is not a 'safe' mutation. This non-conservative amino acid substitution might be associated with susceptibility to type 2 diabetes in OLETF rats.
International Union of Biochemistry and Molecular Biology Life 10/2003; 55(9):533-7. · 3.51 Impact Factor
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ABSTRACT: A genomic region between D1Wox8 and D1Rat90 on rat chromosome 1 was previously shown to be linked to intramuscular fat accumulation by quantitative trait locus (QTL) analysis using a F2 population derived from the Otsuka Long-Evans Tokushima Fatty (OLETF) rat, which exhibits an increase in the levels of intramuscular fat content in Musculus longissimus, and the F344 rat. There exist two regions showing major and minor lod peaks for linkage to intramuscular fat accumulation, in the chromosomal region. We constructed a congenic strain introgressing the OLETF allele on the minor but not the major lod peak region in the F344 rat strain. The congenic strain had higher levels of intramuscular fat content in Musculus longissimus than the inbred partner F344 rat, thereby proving the existence of a QTL, designated Imfm (for Intramuscular fat-minor), responsible for the intramuscular fat accumulation in the congenic region of the minor lod peak region of about 10 cM. The F344.OLETF-Imfm congenic strain might provide a refined tool for the analysis of the gene causing intramuscular fat accumulation.
Experimental Animals 08/2003; 52(4):303-8. · 0.92 Impact Factor
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Kenichi Sogawa,
Takahisa Yamada,
Tomoki Sumida,
Hiroyuki Hamakawa,
Hiroko Kuwabara,
Masahiro Matsuda,
Youji Muramatsu, Hiroyuki Kose,
Kozo Matsumoto,
Yoshiyuki Sasaki,
Koichi Okutani,
Kazuya Kondo,
Yasumasa Monden
Life Sciences 11/2002; 71(21):2575. · 2.53 Impact Factor
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ABSTRACT: The Otuska Long-Evans Tokushima Fatty (OLETF) rat is one of the well-characterized animal models for the study of type 2 diabetes. Our previous QTL mapping identified 11 loci responsible for non-insulin-dependent diabetes mellitus (NIDDM) susceptibility in the OLETF rat. Here we generated a series of congenic animals by individually introgressing all 11 OLETF-derived NIDDM loci into a normoglycemic F344 background. Subsequent oral glucose tolerance test revealed that the congenic strains for Nidd1/of, Nidd2/of, Nidd3/of Nidd4/of, Nidd7/of, and Nidd10/of showed significantly higher levels of blood glucose in comparison with parental host strain F344. Furthermore, simultaneously made heterozygote animals for Nidd1/of and Nidd2/of did not increase blood glucose levels, indicating that these loci are recessively inherited as predicted by the QTL analysis. Congenic strains for the other five loci-Nidd5/of, Nidd6/of, Nidd8/of, Nidd9/of, and Nidd11/of-were apparently normoglycemic, presumably owing to heterosis or because the effect of these loci may not be detected unless interactions with other OLETF genes exist. We believe that these congenic strains should provide useful agents for decomposing complex diabetic traits and for positional cloning.
Mammalian Genome 11/2002; 13(10):558-62. · 2.89 Impact Factor
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ABSTRACT: The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese type 2 diabetes. We showed that the OLETF rat exhibits higher levels of intramuscular fat content in Musculus longissimus as compared to the Fischer-344 (F344) rat. Our investigation was designed to identify quantitative trait loci (QTLs) contributing to the increased levels of intramuscular fat content by performing a whole-genome search using 108 F2 intercross obtained by mating the OLETF and the F344 rats. We identified one QTL responsible for intramuscular fat accumulation on rat chromosome 1 with a maximum lod score of 3.4, which accounts for 5% of the total variance. As expected, the OLETF allele corresponds to the increased levels of intramuscular fat content.
Journal of Veterinary Medical Science 02/2002; 64(1):45-50. · 0.85 Impact Factor
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ABSTRACT: A quantitative trait locus (QTL) responsible for intramuscular fat accumulation in Musculus longissimus of Otsuka Long-Evans Tokushima Fatty (OLETF) rat, Imfm, was previously mapped to the approximately 10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 using Imfm congenic strain. In this study, we refined the Imfm region to a approximately 2.3-cM genomic region between D1Rat225 and D1Rat90, using 12 informative recombinants selected from 176 (Imfm congenic x F344) F, x Imfm congenic backcross progenies. Among 46 genes located within the approximately 2.3-cM region, pancreatic lipase gene, Pnlip, that is a possible candidate for obesity QTL, Nidd6/of, was thought to be the most prominent and physiologically relevant positional candidate for the Imfm QTL. It was previously showed that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5'-flanking region than normal alleles. We found complete cosegregation of the Imfm QTL with Pnlip VNTR in the 12 informative recombinants, suggesting that Pnlip is also a possible candidate for the Imfm QTL.
Research communications in molecular pathology and pharmacology 120-121(1-6):23-31.
