The IA-2 gene family: homologs in Caenorhabditis elegans, Drosophila and zebrafish.
OBJECTIVE
IA-2 and IA-2beta are major autoantigens in Type I (insulin-dependent) diabetes mellitus and are expressed in neuroendocrine tissues including the brain and pancreatic islets of Langerhans. Based on sequence analysis, IA-2 and IA-2beta are transmembrane protein tyrosine phosphatases but lack phosphatase activity because of critical amino acid substitutions in the catalytic domain. We studied the evolutionary conservation of IA-2 and IA-2beta genes and searched for homologs in non-mammalian vertebrates and invertebrates.


METHODS
IA-2 from various species was identified from EST sequences or cloned from cDNA libraries or both. Expression in tissues was determined by transfection and in situ hybridization.


RESULTS
We identified homologs of IA-2 in C. elegans, Drosophila, and zebrafish which showed 46, 58 and 82 % identity and 60, 65 and 87 % similarity, respectively, to the amino acids of the intracellular domain of human IA-2. Further studies showed that IA-2 was expressed in the neural tissues of the three species. Comparison of the genomic structure of the intracellular domain of human IA-2 with that of human IA-2beta showed that they were nearly identical and comparison of the intron-exon boundaries of Drosophila IA-2 with human IA-2 and IA-2beta showed a high degree of relatedness.


CONCLUSIONS
Based on these findings and sequence analysis of IA-2 homologs in mammals, we conclude that there is an IA-2 gene family which is a part of the larger protein tyrosine phosphatase superfamily. The IA-2 and IA-2beta genes represent two distinct subgroups within the IA-2 family which originated over 500 million years ago, long before the development of the pancreatic islets of Langerhans.
Cai
T
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Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4322, USA.
Krause
M W
MW
Odenwald
W F
WF
Toyama
R
R
Notkins
A L
AL
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens; D017173:Caenorhabditis elegans / Q000235:genetics*; D004330:Drosophila / Q000235:genetics*; D015870:Gene Expression; D049452:Green Fluorescent Proteins; D006801:Humans; D017403:In Situ Hybridization; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008565:Membrane Proteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009417:Nerve Tissue / Q000276:immunology; D009474:Neurons / Q000737:chemistry; D010802:Phylogeny; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D016415:Sequence Alignment; D014018:Tissue Distribution; D014162:Transfection; D015027:Zebrafish / Q000235:genetics*
D001324:Autoantigens; D008164:Luminescent Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins; C516862:PTPRN protein, human; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8