Identification of a structurally distinct CD101 molecule encoded in the 950-kb Idd10 region of NOD mice.
Genes affecting autoimmune type 1 diabetes susceptibility in the nonobese diabetic (NOD) mouse (Idd loci) have been mapped using a congenic strain breeding strategy. In the present study, we used a combination of BAC clone contig construction, polymorphism analysis of DNA from congenic strains, and sequence mining of the human orthologous region to generate an integrated map of the Idd10 region on mouse chromosome 3. We found seven genes and one pseudogene in the 950-kb Idd10 region. Although all seven genes in the interval are Idd10 candidates, we suggest the gene encoding the EWI immunoglobulin subfamily member EWI-101 (Cd101) as the most likely Idd10 candidate because of the previously reported immune-associated properties of the human CD101 molecule. Additional support for the candidacy of Cd101 is the presence of 17 exonic single-nucleotide polymorphisms that differ between the NOD and B6 sequences, 10 causing amino acid substitutions in the predicted CD101 protein. Four of these 10 substitutions are nonconservative, 2 of which could potentially alter N-linked glycosylation. Considering our results together with those previous reports that antibodies recognizing human CD101 modulate human T-cell and dendritic cell function, there is now justification to test whether the alteration of CD101 function affects autoimmune islet destruction.
Penha-Gonçalves
Carlos
C
Juvenile Diabetes Research Foundation/Wellcome Trust (JDRF/WT) Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2XY, U.K.
Moule
Carolyn
C
Smink
Luc J
LJ
Howson
Joanna
J
Gregory
Simon
S
Rogers
Jane
J
Lyons
Paul A
PA
Suttie
Joseph J
JJ
Lord
Christopher J
CJ
Peterson
Laurence B
LB
Todd
John A
JA
Wicker
Linda S
LS
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005091:Exons; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011544:Pseudogenes
D015703:Antigens, CD; C093213:CD101 antigen, human; D005819:Genetic Markers; D008562:Membrane Glycoproteins