- Publikační typ
- abstrakt z konference MeSH
Metabolic syndrome (MetS) is an important cause of worldwide morbidity and mortality. Its complex pathogenesis includes, on the one hand, sedentary lifestyle and high caloric intake, and, on the other hand, there is a clear genetic predisposition. PD (Polydactylous rat) is an animal model of hypertriglyceridemia, insulin resistance, and obesity. To unravel the genetic and pathophysiologic background of this phenotype, we compared morphometric and metabolic parameters as well as liver transcriptomes among PD, spontaneously hypertensive rat, and Brown Norway (BN) strains fed a high-fat diet (HFD). After 4 weeks of HFD, PD rats displayed marked hypertriglyceridemia but without the expected hepatic steatosis. Moreover, the PD strain showed significant weight gain, including increased weight of retroperitoneal and epididymal fat pads, and impaired glucose tolerance. In the liver transcriptome, we found 5480 differentially expressed genes, which were enriched for pathways involved in fatty acid beta and omega oxidation, glucocorticoid metabolism, oxidative stress, complement activation, triacylglycerol and lipid droplets synthesis, focal adhesion, prostaglandin synthesis, interferon signaling, and tricarboxylic acid cycle pathways. Interestingly, the PD strain, contrary to SHR and BN rats, did not express the Acsm3 (acyl-CoA synthetase medium-chain family member 3) gene in the liver. Together, these results suggest disturbances in fatty acid utilization as a molecular mechanism predisposing PD rats to hypertriglyceridemia and fat accumulation.
- MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- exprese genu MeSH
- hypertriglyceridemie krev genetika MeSH
- játra metabolismus MeSH
- koenzym A-ligasy genetika MeSH
- krysa rodu rattus MeSH
- modely nemocí na zvířatech MeSH
- nitrobřišní tuk metabolismus MeSH
- polydaktylie MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- stanovení celkové genové exprese metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Metabolic syndrome and one of its manifestations, essential hypertension, is an important cause of worldwide morbidity and mortality. Morbidity and mortality associated with hypertension are caused by organ complications. Previously we revealed a decrease of blood pressure and an amelioration of cardiac fibrosis in a congenic line of spontaneously hypertensive rats (SHR), in which a short segment of chromosome 8 (encompassing only 7 genes) was exchanged for a segment of normotensive polydactylous (PD) origin. To unravel the genetic background of this phenotype we compared heart transcriptomes between SHR rat males and this chromosome 8 minimal congenic line (PD5). We found 18 differentially expressed genes, which were further analyzed using annotations from Database for Annotation, Visualization and Integrated Discovery (DAVID). Four of the differentially expressed genes (Per1, Nr4a1, Nr4a3, Kcna5) belong to circadian rhythm pathways, aldosterone synthesis and secretion, PI3K-Akt signaling pathway and potassium homeostasis. We were also able to confirm Nr4a1 2.8x-fold upregulation in PD5 on protein level using Western blotting, thus suggesting a possible role of Nr4a1 in pathogenesis of the metabolic syndrome.
- MeSH
- fenotyp MeSH
- fibróza MeSH
- funkce levé komory srdeční genetika MeSH
- genetická predispozice k nemoci MeSH
- hypertenze genetika metabolismus patofyziologie MeSH
- kardiomyopatie genetika metabolismus patologie MeSH
- krevní tlak genetika MeSH
- metabolický syndrom genetika metabolismus patofyziologie MeSH
- modely nemocí na zvířatech MeSH
- potkani inbrední SHR MeSH
- regulace genové exprese MeSH
- remodelace komor genetika MeSH
- signální transdukce genetika MeSH
- srdeční komory metabolismus patologie MeSH
- stanovení celkové genové exprese * MeSH
- transkriptom * MeSH
- zvířata kongenní MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Cíl studie: Prezentace výsledků molekulárně genetických vyšetření u mužů s poruchami reprodukce se zaměřením na výzkum úseků DNA a genů ovlivňujících spermatogenezi. Typ studie: Původní práce. Název a sídlo pracoviště: Ústav biologie a lékařské genetiky 1. LF UK a VFN Praha. Metodika: U 123 mužů s poruchami reprodukce jsme provedli rutinní laboratorní diagnostiku, tj. cytogenetické vyšetření, molekulárně genetické vyšetření mutací v CFTR genu a diagnostiku mikrodelecí chromozomu Y. U 107 pacientů bez záchytu patologie výše uvedeným rutinním vyšetřením jsme vyšetřili mikrodelece chromozomu X (CNV64, CNV67, CNV69) a vybrané geny ovlivňující spermatogenezi (AGFG1, CAPZA3, CNTROB, HOOK1, GOPC, SPATA16). Výsledky: U postižených mužů jsme neprokázali negativní vliv vybraných mikrodelecí chromozomu X na spermatogenezi. V rámci vyšetřovaných šesti genů jsme nalezli u dvou pacientů v genu SPATA16 homozygotní haplotyp [1526C>T + 1577T>C], který je pravděpodobně odpovědný za neplodnost obou vyšetřovaných mužů. Závěr: Podle našich vyšetření není účelné zavádět do rutinní diagnostiky vyšetření mikrodelecí chromozomu X v oblastech CNV64, CNV67 a CNV69. Pokud jde o vybrané geny ovlivňující spermatogenezi, naše výsledky ukázaly, že homozygotní haplotyp [1526C>T + 1577T>C] v genu SPATA16 je velmi pravděpodobně zodpovědný za neplodnost u dvou našich pacientů. Zmíněný haplotyp zasluhuje pozornost při vyšetřování mužské neplodnosti.
Objective: To present the results of molecular genetics analysis in men with reproductive disorders focusing on the DNA segments and genes which affect spermatogenesis. Design: Original article. Setting: Institute of Biology and Medical Genetics of the First Faculty of Medicine and General Teaching Hospital, Prague. Methods: One hundred and twenty-three patients identified with a fertility disorder were screened for mutations of the CFTR gene. In all patients were performed cytogenic analysis and assessment of Y-chromosome microdeletions. In 107 patients where the fertility was not detected by routine examination we performed an analysis for X-chromosome microdeletions (CNV64, CNV67, CNV69) and in certain genes necessary for normal spermatogenesis (AGFG1, CAPZA3, CNTROB, HOOK1, GOPC, SPATA16). Results: Our results did not reveal any negative efffects of X-chromosome microdeletion on spermatogenesis. Analysis of six genes showed in two patients in gene SPATA16 a homozygotic haplotype [1526C>T + 1577T>C] which can be most probably responsible for the fertility in two examined patients. Conclusion: According to our results we do not recommend introduction of X-chromosome microdeletions assays in areas CNV64 , CNV67 and CNV69 into routine diagnostic. Regarding the selected genes affecting spermatogenesis, our results showed that homozygotic haplotype [ 1526C>T + 1577T>C] in SPATA16 gene is very likely responsible for infertility in two of our patients. The above mentioned haplotype deserves attention in the investigation of male infertility.
- Klíčová slova
- gen AGFG1, gen CAPZA3, gen CNTROB, gen HOOK1, gen GOPC, gen SPATA16,
- MeSH
- chromozom X patologie MeSH
- chromozomální delece MeSH
- cytogenetické vyšetření MeSH
- DNA analýza MeSH
- klinické laboratorní techniky metody MeSH
- lidé MeSH
- mutace genetika MeSH
- mužská infertilita * diagnóza genetika MeSH
- spermatogeneze * genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
In the inbred SHR/OlaIpcv rat colony, we identified males with small testicles and inability to reproduce. By selectively breeding their parents, we revealed the infertility to segregate as an autosomal recessive Mendelian character. No other phenotype was observed in males, and females were completely normal. By linkage using a backcross with Brown Norway strain, we mapped the locus to a 1.2Mbp segment on chromosome 7, harboring 35 genes. Sequencing of candidate genes revealed a G to A substitution in a canonical 'AG' splice site of intron 37 in Sbf1 (SET binding factor 1, alias myotubularin-related protein 5). This leads to either skipping exon 38 or shifting splicing one base downstream, invariantly resulting in frameshift, premature stop codon and truncation of the protein. Western blotting using two anti-Sbf1 antibodies revealed absence of the full-length protein in the mutant testis. Testicles of the mutant males were significantly smaller compared with SHR from 4weeks, peaked at 84% wild-type weight at 6weeks and declined afterward to 28%, reflecting massive germ cell loss. Histological examination revealed lower germ cell number; latest observed germ cell stage were round spermatids, resulting in the absence of sperm in the epididymis (azoospermia). SBF1 is a member of a phosphatase family lacking the catalytical activity. It probably modulates the activity of a phosphoinositol phosphatase MTMR2. Human homozygotes or compound heterozygotes for missense SBF1 mutations exhibit Charcot-Marie-Tooth disease (manifested mainly as progressive neuropathy), while a single mouse knockout reported in the literature identified male infertility as the only phenotype manifestation.
- MeSH
- alternativní sestřih genetika MeSH
- intracelulární signální peptidy a proteiny genetika MeSH
- krysa rodu rattus MeSH
- mutace genetika MeSH
- mužská infertilita etiologie metabolismus patologie MeSH
- potkani inbrední SHR MeSH
- regulace genové exprese * MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
