title: A novel Dock8 gene mutation confers diabetogenic susceptibility in the LEW.1AR1/Ztm-iddm rat, an animal model of human type 1 diabetes.
abstract: OBJECTIVE
  The LEW.1AR1-iddm rat, an animal model of human type 1 diabetes, arose through a spontaneous mutation within the inbred strain LEW.1AR1. A susceptibility locus (Iddm8) on rat chromosome 1 (RNO1) has been identified previously, which is accompanied by autoimmune diabetes and the additional phenotype of a variable CD3(+) T cell frequency.
  
  
  METHODS
  In the present study we characterised the Iddm8 region on RNO1 in backcross strains using the genetically divergent Brown Norway (BN) and Paris (PAR) rats. Candidate genes of the Iddm8 region were sequenced for mutation analysis.
  
  
  RESULTS
  The Iddm8 region could be subdivided by single nucleotide polymorphism (SNP) analyses. In the first region, a mutation in exon 44 of the Dock8 gene was identified resulting in an amino acid exchange in the protein from glutamine to glutamate. This exchange is unique for the LEW.1AR1-iddm rat. In the second region, a SNP was detected in exon 11 of the Vwa2 gene with an exchange from arginine to tryptophan. This SNP is also present in other rat strains.
  
  
  CONCLUSIONS
  The Dock8 mutation gave rise to a new type 1 diabetes rat model with very close similarity to type 1 diabetes in humans, providing a deepened insight into the impact of genes involved in diabetes development.
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Arndt
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, 30623, Hannover, Germany. wedekind.dirk@mh-hannover.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Jörns
authors.affiliation: Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Tsiavaliaris
authors.affiliation: Centre for Biomedical Genetics, Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Institute for Laboratory Animal Science, Hannover Medical School, 30623, Hannover, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.affiliation: Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany. lenzen.sigurd@mh-hannover.de.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lenzen
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005091:Exons / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural; D008958:Models, Molecular; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011917:Rats, Inbred Lew; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: C000610071:Dock8 protein, rat; D020662:Guanine Nucleotide Exchange Factors; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014841:von Willebrand Factor
keywords: Animal model; Mutation; T cells; Type 1 diabetes