Aec2^C57BL/6J
QTL Variant Detail

Summary

• QTL variant: Aec2^C57BL/6J
• Name: autoimmune exocrinopathy 2; C57BL/6J
• MGI ID: MGI:3769160
• QTL: Aec2 Location: Chr1:52457737-182250592 bp Genetic Position: Chr1, Syntenic

Variant origin

• Strain of Specimen: C57BL/6J

Variant description

• Allele Type: QTL

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:128900

Previously identified diabetes QTLs Idd3 (Chr3) and Idd5 (Chr1) also show linkage to autoimmune exocrinopathy, a symptom of Sjogren's syndrome. Authors investigated the effect of these QTLs in congenic lines carrying NOD/Uf-derived Idd3 and/or Idd5 donor regions on a C57BL/6J genetic background. Parental strain NOD/Uf is susceptible to sialadenitis compared to C57BL/6J. Congenic animals were phenotyped at 12- and 16-weeks of age.

Single congenic lines B6.NOD-Idd3 and B6.NOD-Idd5 did not display significant susceptibility to autoimmune exocrinopathy. However, the double congenic line B6.NOD-Idd3^NOD/Uf Idd5^NOD/Uf displays decreased secretory function starting at 16 weeks of age, decreased salivary flow rates, and reduced amylase activity. Authors noted that the reciprocal congenic line NOD.B6-Idd3^C57BL/6J Idd5^C57BL/6J restored normal secretory function comparable to that of resistant strain C57BL/6J.

The autoimmune exocrinopathy susceptibility locus captured within the Idd3 interval on Chromosome 3 was named Aec1 (autoimmune exocrinopathy 1) by the authors. A potential candidate gene is Il2 (19.2 cM).

The susceptibility locus on Chromosome 1 captured within the Idd5 interval was named Aec2. Potential candidate genes for Aec2 include Fn1 (36.1 cM), Igfbp2 (36.1 cM), Igfbp5 (36.1cM), Col6a3 (53.9 cM), Btg2 (71 cM), Il10 (69.9 cM), Lamc1 (81.1 cM), and Lamc2 (81.1 cM).

J:129916

Authors investigated the effects of diabetes susceptibility loci Idd3 (Chr3) and Idd5 (Chr1) on the associated phenotype autoimmune exocrinopathy in B6.NOD-Idd3^NOD/Uf Idd5^NOD/Uf and B6.NOD-Idd5^NOD/Uf congenic animals. Parental strain NOD/Uf displays lymphocyte infiltration of the exocrine glands and loss of salivary secretory function.

The single congenic strain B6.NOD-Idd5^NOD/Uf exhibits autoimmune exocrinopathy but does not display loss of secretory function. This suggests a gene on Chromosome 1 captured within the congenic interval specifically influences lymphocytic infiltration of the exocrine glands. This locus was named Aec2 (autoimmune exocrinopathy 2) in a previous publication. Potential candidate genes located in this interval include Il1r1 (19.5 cM), Bcl2 (59.8 cM), Casp8 (30.1 cM), and Ctla4 (30.1 cM).

In the double congenic B6.NOD-Idd3^NOD/Uf Idd5^NOD/Uf decreased saliva flow was observed at 12 weeks of age. Saliva flow was reduced by 41% compared to 20-week old control C57BL/6J animals. This finding suggests NOD/Uf-derived genes captured in the Idd3 and Idd5 donor intervals recapitulate the salivary dysfunction phenotype of Sjogren syndrome. The locus linked to Idd3 was named Aec1 (autoimmune exocrinopathy 1) in a previous publication. Il2 (19.2 cM) is a possible candidate gene for Aec1.

J:129282

Susceptibility loci for autoimmune exocrinopathy (Aec1 and Aec2) previously mapped to mouse Chromosomes 3 and 1 overlapping with diabetes susceptibility loci Idd3 and Idd5, respectively. The Aec1 locus extends from the centromere (D3Mit164) to 48.5 cM (Tshb) on chromosome 3. Authors studied Sjogren syndrome-like exocrinopathy phenotypes in a susceptible double congenic mouse line (B6.NOD-Aec1^NOD/ShiLt Aec2^NOD/ShiLt) in which recombination had occurred within the Aec1 (autoimmune exocrinopathy 1) at 19.5 cM near D3Mit151. This new line is referred to as B6.NOD-Aec1R1Aec2 and carries NOD/ShiLt-derived DNA from the chromosome 3 centromere to 19.5 cM for Aec1 and from 32 cM (D1Mit18) to 101 cM (D1Mit360) for Aec2 on chromosome 1 on a C57BL/6J genetic background.

The subcongenic line displays lacrimal and salivary gland pathology similar to the original congenic line. Subcongenic animals develop sialadenitis by 10 weeks of age in males and by 19 weeks of age in females, with a more severe phenotype in the females. Both sexes display a 35-40% reduction in salivary flow rate at age 5-19 weeks for males and age 5-22 weeks for females. Salivary amylase activity also showed significant decline by age 19-22 weeks in both sexes. Interestingly, males develop severe lacrimal gland inflammation and loss of secretory function where as females do not. Anti-nuclear antibody production was present in male subcongenic animals as early as age 5 weeks but was not present in female subcongenic animals until age 10 weeks.

Il2 (19.2 cM, chr3) is an attractive candidate gene for Aec1. This gene is located near the recombination breakpoint and is associated with susceptibility to autoimmune diseases, such as ulcerative colitis and rheumatoid arthritis. Other potential candidate genes in the Aec1 interval include Il7 (6.6 cM), Car1 (10.5 cM), Car2 (10.5 cM), Car3 (11.7 cM), Gpr177 (formerly Evi, 14.4 cM), Fim3 (14.4 cM), Mpmv20 (13.8 cM), Mtv56 (7.5 cM), and Pad4 (10 cM).

References

• Original: J:128900 Cha S, et al., Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjogren's syndrome) on a healthy murine background. Arthritis Rheum. 2002 May;46(5):1390-8
• All: 9 reference(s)