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Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice.

Fraser HI, Howlett S, Clark J, Rainbow DB, Stanford SM, Wu DJ, Hsieh YW, Maine CJ, Christensen M, Kuchroo V, Sherman LA, Podolin PL, Todd JA, Steward CA, Peterson LB, Bottini N, Wicker LS - J. Immunol. (2015)

Bottom Line: In this study, we define two additional Idd loci-Idd18.2 and Idd18.4-within the boundaries of this cluster of disease-associated genes.The human ortholog of Ptpn22, PTPN22, is associated with numerous autoimmune diseases, including T1D.Functional studies showed higher expression of full-length Ptpn22 RNA and protein, and decreased TCR signaling in congenic strains with B6-derived Idd18.2 susceptibility alleles.

View Article: PubMed Central - PubMed

Affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom;

No MeSH data available.


Related in: MedlinePlus

Idd18.2 and Idd18.4 annotation and sequence polymorphisms in NCBIM37. (A) The congenic boundaries of line 8010 define the Idd18.4 locus, and the centromeric boundary of line R8 and the telomeric boundary of line 7848 define the Idd18.2 locus. The T1DBase Gene Span track displays the maximum genomic interval for each gene: candidate genes are displayed in green, blue indicates other protein-encoding genes, and yellow indicates small cytoplasmic RNA genes. The NOD TilePath track represents the sequenced NOD BAC clones, and the NOD_BAC_SNP_graph represents the SNP density per 10 kb, detected by comparing the NOD BAC clone sequence to the B6 reference sequence. The NOD_NGS_SNP_graph displays the SNP density per 10 kb of SNPs detected between the NCBIM37 B6 reference sequence and NOD/ShiLtJ NGS data. (B and C) The coding sequences of the transcripts from the Idd18.2 and Idd18.4 candidate genes Ptpn22 and Cd2 are shown, respectively, in the T1DBase Curated Transcripts track. The SNPs surrounding these genes are shown underneath. These SNPs have been detected by comparing the B6 reference sequence to either the NOD BAC clone sequence (NOD Variation track) or the NOD/ShiLtJ NGS data (NGS NOD SNPs track). Black, red, blue, and green lines represent G, T, C, and A NOD alleles, respectively. The NGS data also contain ambiguous bases. R, Y, M, K, W, and S are represented as brown, orange, pink, cyan, gold and gray lines, respectively. Yellow lines are SNPs where the base information is unknown. Note that where multiple SNPs are located close together in these two tracks, the lines in the NOD variation or NGS NOD SNPs track may represent more than one SNP. There is a higher SNP density over Ptpn22; to represent this density better, the NOD_BAC_SNP_graph and NOD NGS_SNP_graph display the density of SNPs per 10 kb.
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fig02: Idd18.2 and Idd18.4 annotation and sequence polymorphisms in NCBIM37. (A) The congenic boundaries of line 8010 define the Idd18.4 locus, and the centromeric boundary of line R8 and the telomeric boundary of line 7848 define the Idd18.2 locus. The T1DBase Gene Span track displays the maximum genomic interval for each gene: candidate genes are displayed in green, blue indicates other protein-encoding genes, and yellow indicates small cytoplasmic RNA genes. The NOD TilePath track represents the sequenced NOD BAC clones, and the NOD_BAC_SNP_graph represents the SNP density per 10 kb, detected by comparing the NOD BAC clone sequence to the B6 reference sequence. The NOD_NGS_SNP_graph displays the SNP density per 10 kb of SNPs detected between the NCBIM37 B6 reference sequence and NOD/ShiLtJ NGS data. (B and C) The coding sequences of the transcripts from the Idd18.2 and Idd18.4 candidate genes Ptpn22 and Cd2 are shown, respectively, in the T1DBase Curated Transcripts track. The SNPs surrounding these genes are shown underneath. These SNPs have been detected by comparing the B6 reference sequence to either the NOD BAC clone sequence (NOD Variation track) or the NOD/ShiLtJ NGS data (NGS NOD SNPs track). Black, red, blue, and green lines represent G, T, C, and A NOD alleles, respectively. The NGS data also contain ambiguous bases. R, Y, M, K, W, and S are represented as brown, orange, pink, cyan, gold and gray lines, respectively. Yellow lines are SNPs where the base information is unknown. Note that where multiple SNPs are located close together in these two tracks, the lines in the NOD variation or NGS NOD SNPs track may represent more than one SNP. There is a higher SNP density over Ptpn22; to represent this density better, the NOD_BAC_SNP_graph and NOD NGS_SNP_graph display the density of SNPs per 10 kb.

Mentions: The locus delineated by lines 7848 and 8010 (Fig. 1A) overlaps with the Idd18.2 locus delineated by line R8 (Fig. 1A). As both loci contain Idd18.2, the Idd18.2 locus is, therefore, located between the centromeric recombination point in line R8 (between AC122219_3 and R8_p_SNP_1) and the telomeric recombination point in line 7848 (between Magi3 and Susc_96.62; Fig. 1A). Therefore, Idd18.2 is a 1.31-Mb locus between, but not including, the microsatellite markers AC122219_3 and Susc_96.62 (Fig. 1A), and contains only 18 protein-encoding genes, including the candidate Ptpn22 (Fig. 2A).


Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice.

Fraser HI, Howlett S, Clark J, Rainbow DB, Stanford SM, Wu DJ, Hsieh YW, Maine CJ, Christensen M, Kuchroo V, Sherman LA, Podolin PL, Todd JA, Steward CA, Peterson LB, Bottini N, Wicker LS - J. Immunol. (2015)

Idd18.2 and Idd18.4 annotation and sequence polymorphisms in NCBIM37. (A) The congenic boundaries of line 8010 define the Idd18.4 locus, and the centromeric boundary of line R8 and the telomeric boundary of line 7848 define the Idd18.2 locus. The T1DBase Gene Span track displays the maximum genomic interval for each gene: candidate genes are displayed in green, blue indicates other protein-encoding genes, and yellow indicates small cytoplasmic RNA genes. The NOD TilePath track represents the sequenced NOD BAC clones, and the NOD_BAC_SNP_graph represents the SNP density per 10 kb, detected by comparing the NOD BAC clone sequence to the B6 reference sequence. The NOD_NGS_SNP_graph displays the SNP density per 10 kb of SNPs detected between the NCBIM37 B6 reference sequence and NOD/ShiLtJ NGS data. (B and C) The coding sequences of the transcripts from the Idd18.2 and Idd18.4 candidate genes Ptpn22 and Cd2 are shown, respectively, in the T1DBase Curated Transcripts track. The SNPs surrounding these genes are shown underneath. These SNPs have been detected by comparing the B6 reference sequence to either the NOD BAC clone sequence (NOD Variation track) or the NOD/ShiLtJ NGS data (NGS NOD SNPs track). Black, red, blue, and green lines represent G, T, C, and A NOD alleles, respectively. The NGS data also contain ambiguous bases. R, Y, M, K, W, and S are represented as brown, orange, pink, cyan, gold and gray lines, respectively. Yellow lines are SNPs where the base information is unknown. Note that where multiple SNPs are located close together in these two tracks, the lines in the NOD variation or NGS NOD SNPs track may represent more than one SNP. There is a higher SNP density over Ptpn22; to represent this density better, the NOD_BAC_SNP_graph and NOD NGS_SNP_graph display the density of SNPs per 10 kb.
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fig02: Idd18.2 and Idd18.4 annotation and sequence polymorphisms in NCBIM37. (A) The congenic boundaries of line 8010 define the Idd18.4 locus, and the centromeric boundary of line R8 and the telomeric boundary of line 7848 define the Idd18.2 locus. The T1DBase Gene Span track displays the maximum genomic interval for each gene: candidate genes are displayed in green, blue indicates other protein-encoding genes, and yellow indicates small cytoplasmic RNA genes. The NOD TilePath track represents the sequenced NOD BAC clones, and the NOD_BAC_SNP_graph represents the SNP density per 10 kb, detected by comparing the NOD BAC clone sequence to the B6 reference sequence. The NOD_NGS_SNP_graph displays the SNP density per 10 kb of SNPs detected between the NCBIM37 B6 reference sequence and NOD/ShiLtJ NGS data. (B and C) The coding sequences of the transcripts from the Idd18.2 and Idd18.4 candidate genes Ptpn22 and Cd2 are shown, respectively, in the T1DBase Curated Transcripts track. The SNPs surrounding these genes are shown underneath. These SNPs have been detected by comparing the B6 reference sequence to either the NOD BAC clone sequence (NOD Variation track) or the NOD/ShiLtJ NGS data (NGS NOD SNPs track). Black, red, blue, and green lines represent G, T, C, and A NOD alleles, respectively. The NGS data also contain ambiguous bases. R, Y, M, K, W, and S are represented as brown, orange, pink, cyan, gold and gray lines, respectively. Yellow lines are SNPs where the base information is unknown. Note that where multiple SNPs are located close together in these two tracks, the lines in the NOD variation or NGS NOD SNPs track may represent more than one SNP. There is a higher SNP density over Ptpn22; to represent this density better, the NOD_BAC_SNP_graph and NOD NGS_SNP_graph display the density of SNPs per 10 kb.
Mentions: The locus delineated by lines 7848 and 8010 (Fig. 1A) overlaps with the Idd18.2 locus delineated by line R8 (Fig. 1A). As both loci contain Idd18.2, the Idd18.2 locus is, therefore, located between the centromeric recombination point in line R8 (between AC122219_3 and R8_p_SNP_1) and the telomeric recombination point in line 7848 (between Magi3 and Susc_96.62; Fig. 1A). Therefore, Idd18.2 is a 1.31-Mb locus between, but not including, the microsatellite markers AC122219_3 and Susc_96.62 (Fig. 1A), and contains only 18 protein-encoding genes, including the candidate Ptpn22 (Fig. 2A).

Bottom Line: In this study, we define two additional Idd loci-Idd18.2 and Idd18.4-within the boundaries of this cluster of disease-associated genes.The human ortholog of Ptpn22, PTPN22, is associated with numerous autoimmune diseases, including T1D.Functional studies showed higher expression of full-length Ptpn22 RNA and protein, and decreased TCR signaling in congenic strains with B6-derived Idd18.2 susceptibility alleles.

View Article: PubMed Central - PubMed

Affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom;

No MeSH data available.


Related in: MedlinePlus