title: Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.
abstract: 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.
authors.affiliation: Robert H. Williams Laboratory, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Armand J
authors.initials: AJ
authors.lastname: MacMurray
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Moralejo
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Rutledge
authors.forename: Brian
authors.initials: B
authors.lastname: Van Yserloo
authors.forename: Paul
authors.initials: P
authors.lastname: Gohlke
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Speros
authors.forename: Ben
authors.initials: B
authors.lastname: Snyder
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schaefer
authors.forename: Sabine
authors.initials: S
authors.lastname: Bieg
authors.forename: Jianjie
authors.initials: J
authors.lastname: Jiang
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ettinger
authors.forename: Jessica
authors.initials: J
authors.lastname: Fuller
authors.forename: Terri L
authors.initials: TL
authors.lastname: Daniels
authors.forename: Anna
authors.initials: A
authors.lastname: Pettersson
authors.forename: Kimberly
authors.initials: K
authors.lastname: Orlebeke
authors.forename: Bruce
authors.initials: B
authors.lastname: Birren
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Jacob
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
mesh_terms: 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*
chemical_list: 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