Identification of the porcine homologous of human disease causing trinucleotide repeat sequences

Madsen, Lone Bruhn; Thomsen, Bo; Sølvsten, Christina Ane Elisabeth; Berthou, Christian; Fredholm, Merete; Jørgensen, Arne Lund; Nielsen, Anders Lade

doi:10.1007/s10048-007-0088-y

Cited by 8 publications

(3 citation statements)

References 49 publications

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“…A similar result was also demonstrated for porcine HTT [42]. One likely explanation is that the identified bovine polymorphic gene variants represented normal alleles of relatively short lengths and not the extreme expansions characteristic of some poly-Q encoding genes that cause human diseases [1,6,11].…”

Section: Discussionsupporting

confidence: 68%

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

et al. 2010

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BackgroundAbout forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation.ResultsThe current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified.ConclusionsTranscriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.

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Section: Discussionsupporting

confidence: 68%

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

et al. 2010

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“…Nonetheless, they are associated to the same residue biases. Finally, these residues often appear after the polyQs during evolution [47]. For example, the polyP flanking huntingtin's polyQ is found only in mammals not in other vertebrates [45].…”

Section: Discussionmentioning

confidence: 99%

Polyglutamine Repeats Are Associated to Specific Sequence Biases That Are Conserved among Eukaryotes

et al. 2012

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Nine human neurodegenerative diseases, including Huntington's disease and several spinocerebellar ataxia, are associated to the aggregation of proteins comprising an extended tract of consecutive glutamine residues (polyQs) once it exceeds a certain length threshold. This event is believed to be the consequence of the expansion of polyCAG codons during the replication process. This is in apparent contradiction with the fact that many polyQs-containing proteins remain soluble and are encoded by invariant genes in a number of eukaryotes. The latter suggests that polyQs expansion and/or aggregation might be counter-selected through a genetic and/or protein context. To identify this context, we designed a software that scrutinize entire proteomes in search for imperfect polyQs. The nature of residues flanking the polyQs and that of residues other than Gln within polyQs (insertions) were assessed. We discovered strong amino acid residue biases robustly associated to polyQs in the 15 eukaryotic proteomes we examined, with an over-representation of Pro, Leu and His and an under-representation of Asp, Cys and Gly amino acid residues. These biases are conserved amongst unrelated proteins and are independent of specific functional classes. Our findings suggest that specific residues have been co-selected with polyQs during evolution. We discuss the possible selective pressures responsible of the observed biases.

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“…However, streptomycin had side effects on pigs similar to those on humans. 11 Among other animals, primates are genetically closest to humans, but they are expensive and difficult to maintain. Because of their strong genetic, anatomical and physiological similarities with humans, mini pigs have advantages over rodent models as pharmacokinetic models.…”

Section: Discussionmentioning

confidence: 99%

Method used to establish a large animal model of drug-induced acute kidney injury

Wang

Zhang

Cai

et al. 2021

Exp Biol Med (Maywood)

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Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.

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Identification of the porcine homologous of human disease causing trinucleotide repeat sequences

Cited by 8 publications

References 49 publications

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

Polyglutamine Repeats Are Associated to Specific Sequence Biases That Are Conserved among Eukaryotes

Method used to establish a large animal model of drug-induced acute kidney injury

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