Polymorphism analysis of four canine MHC class I genes

Graumann, M.B.; DeRose, Susan; Ostrander, Elaine A.; Storb, Rainer

doi:10.1111/j.1399-0039.1998.tb02976.x

Cited by 53 publications

(67 citation statements)

References 18 publications

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“…Coding DNA coordinates for these variants are c.186C>G and c.196A>G, respectively; c.186C>G causes an F33L substitution and c.196A>G causes a N37D substitution. 3 Together, these variants define the difference between the reference DLA-79 sequence and the DLA-79*001:02 allele that has been previously reported (Graumann et al 1998; Venkataraman et al 2013) and are in perfect linkage disequilibrium across all samples evaluated. We also noted an additional 5 polymorphisms (4 upstream of DLA-79, 1 in intron 1 of DLA-79) in perfect linkage disequilibrium with DLA-79*001:02, but these variants were not validated beyond the original 16 dogs (Figure 2).…”

Section: Resultsmentioning

confidence: 95%

“…Our genotyping assay for DLA-79*001:02 is based on one or two of the seven polymorphic positions in exon 2 and none of the five polymorphic positions in exon 3. The assumption is that this assay will separate DLA-79*001:02 from the other 5 alleles that have been previously identified (Graumann et al 1998; Venkataraman et al 2013). Genotyping was performed by either Sanger sequencing or an endpoint genotyping assay in an additional 173 dogs with various immune-mediated diseases and 206 control dogs (validation cohort 2, Online Resource 1).…”

Section: Methodsmentioning

confidence: 99%

“… 3 Note that the numbering scheme of the cDNA starts at the initiation codon in the canine sequence, however the numbering scheme of the protein is adapted to align with human MHC class I molecules such that the first amino acid in exon 2 is counted as number one (Graumann et al 1998). …”

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confidence: 99%

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Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

et al. 2015

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Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher’s exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12), and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared to the reference allele, DLA-79*001:01) resulting in F33L and N37D amino acid changes. These mutations occur in the peptide binding pocket of the protein, and based upon our computational modeling studies are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly, and to determine the specific mechanism by which the identified variants alter canine immune system function.

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Section: Resultsmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

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Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

et al. 2015

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“…Only four of these seven genes encode functional MHC-complexes, named DLA-12, -64, -79, -88 [12]. DLA-12, -64, and -79 do not show the typical MHC class Ia characteristics, and DLA-79 is currently considered a non-classical MHC molecule [10, 12, 13]. In contrast, DLA-88 is a highly polymorphic MHC class Ia gene which most likely encodes a classical MHC molecule [13, 14].…”

Section: Introductionmentioning

confidence: 99%

“…DLA-12, -64, and -79 do not show the typical MHC class Ia characteristics, and DLA-79 is currently considered a non-classical MHC molecule [10, 12, 13]. In contrast, DLA-88 is a highly polymorphic MHC class Ia gene which most likely encodes a classical MHC molecule [13, 14]. There are 59 DLA-88 alleles known to date [13–18].…”

Section: Introductionmentioning

confidence: 99%

Characterization of the Canine MHC Class I DLA-88*50101 Peptide Binding Motif as a Prerequisite for Canine T Cell Immunotherapy

et al. 2016

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There are limitations in pre-clinical settings using mice as a basis for clinical development in humans. In cancer, similarities exist between humans and dogs; thus, the dog patient can be a link in the transition from laboratory research on mouse models to clinical trials in humans. Knowledge of the peptides presented on MHC molecules is fundamental for the development of highly specific T cell-based immunotherapies. This information is available for human MHC molecules but is absent for the canine MHC. In the present study, we characterized the binding motif of dog leukocyte antigen (DLA) class I allele DLA-88*50101, using human C1R and K562 transfected cells expressing the DLA-88*50101 heavy chain. MHC class I immunoaffinity-purification revealed 3720 DLA-88*50101 derived peptides, which enabled the determination of major anchor positions. The characterized binding motif of DLA-88*50101 was similar to HLA-A*02:01. Peptide binding analyses on HLA-A*02:01 and DLA-88*50101 via flow cytometry showed weak binding of DLA-88*50101 derived peptides to HLA-A*02:01, and vice versa. Our results present for the first time a detailed peptide binding motif of the canine MHC class I allelic product DLA-88*50101. These data support the goal of establishing dogs as a suitable animal model for the evaluation and development of T cell-based cancer immunotherapies, benefiting both dog and human patients.

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Renal Transplantation

Adin¹

2011

Nephrology and Urology of Small Animals

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Polymorphism analysis of four canine MHC class I genes

Cited by 53 publications

References 18 publications

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

Characterization of the Canine MHC Class I DLA-88*50101 Peptide Binding Motif as a Prerequisite for Canine T Cell Immunotherapy

Renal Transplantation

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