Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.
The BB (BioBreeding) rat is one of the best models of spontaneous autoimmune diabetes and is used to study non-MHC loci contributing to Type 1 diabetes. Type 1 diabetes in the diabetes-prone BB (BBDP) rat is polygenic, dependent upon mutations at several loci. Iddm1, on chromosome 4, is responsible for a lymphopenia (lyp) phenotype and is essential to diabetes. In this study, we report the positional cloning of the Iddm1/lyp locus. We show that lymphopenia is due to a frameshift deletion in a novel member (Ian5) of the Immune-Associated Nucleotide (IAN)-related gene family, resulting in truncation of a significant portion of the protein. This mutation was absent in 37 other inbred rat strains that are nonlymphopenic and nondiabetic. The IAN gene family, lying within a tight cluster on rat chromosome 4, mouse chromosome 6, and human chromosome 7, is poorly characterized. Some members of the family have been shown to be expressed in mature T cells and switched on during thymic T-cell development, suggesting that Ian5 may be a key factor in T-cell development. The lymphopenia mutation may thus be useful not only to elucidate Type 1 diabetes, but also in the function of the Ian gene family as a whole.
MacMurray
Armand J
AJ
Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Moralejo
Daniel H
DH
Kwitek
Anne E
AE
Rutledge
Elizabeth A
EA
Van Yserloo
Brian
B
Gohlke
Paul
P
Speros
Sara J
SJ
Snyder
Ben
B
Schaefer
Jonathan
J
Bieg
Sabine
S
Jiang
Jianjie
J
Ettinger
Ruth A
RA
Fuller
Jessica
J
Daniels
Terri L
TL
Pettersson
Anna
A
Orlebeke
Kimberly
K
Birren
Bruce
B
Jacob
Howard J
HJ
Lander
Eric S
ES
Lernmark
Ake
A
D000595:Amino Acid Sequence; D000818:Animals; D020296:Animals, Congenic / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000235:genetics*; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008231:Lymphopenia / Q000209:etiology / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D051381:Rats; D011913:Rats, Inbred BB; D011916:Rats, Inbred F344; D020332:Rats, Inbred LEC; D020334:Rats, Inbred OLETF; D017384:Sequence Deletion / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; C485688:GIMAP4 protein, human; C400051:Ian1 protein, mouse; C516765:PTPN22 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; D017027:Protein Tyrosine Phosphatases; C516766:Ptpn22 protein, mouse; D019204:GTP-Binding Proteins