AUTOANTIBODIES TO PROTEIN-TYROSINE PHOSPHATASE-LIKE PROTEINS IN TYPE-I DIABETES - OVERLAPPING SPECIFICITIES TO PHOGRIN AND ICA512 IA-2/

An insulin granule membrane protein, protein (phosphatase homologue of granules from rat insulinoma), with homology to islet cell antigen (I CA) 512/IA-2 has recently been cloned from an insulinoma cDNA expressi on library with antigranule membrane sera. We have developed a radioim munoassay for detecting anti-phogrin autoantibodies using in vitro tra nscribed and translated phogrin and have established the sensitivity a nd specificity of this assay, Thirty-two of 57 (56%) new-onset patient s with type I diabetes and 26 of 44 (59%) first-degree relatives follo wed to diabetes had anti-phogrin antibody levels exceeding the 99th pe rcentile of 108 normal control subjects. Levels of anti-phogrin autoan tibodies correlated with ICA512/IA-2 autoantibodies (r = 0.82, P < 0.0 001), but minimally with insulin autoantibodies (r = 0.20, P = 0.05) a nd not with GAD65 autoantibodies (r = 0.16, P = 0.12), Ninety-eight pe rcent (57 of 58) of-patients positive for anti-phogrin autoantibodies were also positive for autoantibodies against ICA512/IA-2. Nine percen t (9 of 101) of new-onset patients and relatives followed to diabetes mere ICA512/IA-2 autoantibody-positive but anti-phogrin autoantibody-n egative. Preincubation of sera with recombinant ICA512/IA-2 protein co mpletely for the majority and partially for a minority inhibited bindi ng to in vitro translated phogrin. In three relatives in which ICA512/ IA-2 autoantibodies concerted to positivity with sequential follow-up, anti-phogrin autoantibodies developed at the same time, These results suggest that anti-phogrin and ICA512/IA-2 autoantibodies are related subsets of anti-islet autoantibodies.