Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice.
Insulinoma-associated protein (IA)-2beta, also known as phogrin, is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is located in dense-core secretory vesicles. In patients with type 1 diabetes, autoantibodies to IA-2beta appear years before the development of clinical disease. The genomic structure and function of IA-2beta, however, is not known. In the present study, we determined the genomic structure of IA-2beta and found that both human and mouse IA-2beta consist of 23 exons and span approximately 1,000 and 800 kb, respectively. With this information, we prepared a targeting construct and inactivated the mouse IA-2beta gene as demonstrated by lack of IA-2beta mRNA and protein expression. The IA-2beta(-/-) mice, in contrast to wild-type controls, showed mild glucose intolerance and impaired glucose-stimulated insulin secretion. Knockout of the IA-2beta gene in NOD mice, the most widely studied animal model for human type 1 diabetes, failed to prevent the development of cyclophosphamide-induced diabetes. We conclude that IA-2beta is involved in insulin secretion, but despite its importance as a major autoantigen in human type 1 diabetes, it is not required for the development of diabetes in NOD mice.
Kubosaki
Atsutaka
A
Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4322, USA.
Gross
Steffen
S
Miura
Junnosuke
J
Saeki
Keiichi
K
Zhu
Min
M
Nakamura
Shinichiro
S
Hendriks
Wiljan
W
Notkins
Abner Louis
AL
D000818:Animals; D001324:Autoantigens / Q000235:genetics; D003520:Cyclophosphamide; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005091:Exons; D005260:Female; D017353:Gene Deletion; D016678:Genome; D015894:Genome, Human; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
D001324:Autoantigens; D007166:Immunosuppressive Agents; D007328:Insulin; D008565:Membrane Proteins; D003520:Cyclophosphamide; C102889:PTPRN2 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005947:Glucose