Experiment
84 (BALB/cA x HIGA/Nsc)F2 animals were genotyped at 102 polymorphic loci to identify QTLs associated with polymeric IgA trait and high serum IgA, characteristics of IgA neuropathy. Parental strain HIGA/Nsc is an inbred strain derived from ddY, which has been selected for high serum IgA and is used as a model for human IgA neuropathy. HIGA exhibits high serum IgA from an early age, polymeric IgA dominance, and glomerulonephritis with IgA deposition. Parental strain BALB/cA displays monomeric and dimeric IgA, butnot polymeric IgA.
Linkage to polymeric IgA was detected on mouse Chromosome 12 at which point 168 (BALB/cA x HIGA/Nsc)F2 animals were genotyped for markers in this region. An interval between 53 cM (D12Mit80) and 59 cM (D12Mit150a) showed linkageto polymeric IgA with peak linkage of LOD=15.4 at D12Mit263 (58 cM). This locus is named Plyid and appears to be inherited recessively. A cluster of immunoglobulin heavy chain genes is found in this region and the IgA gene, Igh-2, is located at 58 cM.
Sequence analysis of Igh-2 revealed 18 polymorphic differences between HIGA and BALB/cA, with most of the polymorphisms in the hinge region (8 amino acid differences). The hinge region sequence of HIGA was found to be similar to that of DBA/2J. Western blot analysis showed that DBA/2J displays polymeric IgA dominance similar to HIGA. However DBA/2J did not exhibit elevated serum IgA compared to other inbred strains such as AKR/J, C57BL/6J, and BALB/cA.