Sequence variation and expression of the Gimap gene family in the BB rat.
Positional cloning of lymphopenia (lyp) in the BB rat revealed a frameshift mutation in Gimap5, a member of at least seven related GTPase Immune Associated Protein genes located on rat chromosome 4q24. Our aim was to clone and sequence the cDNA of the BB diabetes prone (DP) and diabetes resistant (DR) alleles of all seven Gimap genes in the congenic DR.lyp rat line with 2 Mb of BB DP DNA introgressed onto the DR genetic background. All (100%) DR.(lyp/lyp) rats are lymphopenic and develop type 1 diabetes (T1D) by 84 days of age while DR.(+/+) rats remain T1D and lyp resistant. Among the seven Gimap genes, the Gimap5 frameshift mutation, a mutant allele that produces no protein, had the greatest impact on lymphopenia in the DR.(lyp/lyp) rat. Gimap4 and Gimap1 each had one amino acid substitution of unlikely significance for lymphopenia. Quantitative RT-PCR analysis showed a reduction in expression of all seven Gimap genes in DR.(lyp/lyp) spleen and mesenteric lymph nodes when compared to DR.(+/+). Only four; Gimap1, Gimap4, Gimap5, and Gimap9 were reduced in thymus. Our data substantiates the Gimap5 frameshift mutation as the primary defect with only limited contributions to lymphopenia from the remaining Gimap genes.
Diabetes and Endocrinology Research Center, University of Washington, Seattle, WA 98109, USA.
Elizabeth A
EA
Rutledge
Jessica M
JM
Fuller
Brian
B
Van Yserloo
Daniel H
DH
Moralejo
Ruth A
RA
Ettinger
Prashant
P
Gaur
Jana L
JL
Hoehna
Morgan R
MR
Peterson
Richard
R
Jensen
Anne E
AE
Kwitek
Ake
A
Lernmark
D000595:Amino Acid Sequence; D000818:Animals; D020296:Animals, Congenic; D001483:Base Sequence; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D016368:Frameshift Mutation; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D015870:Gene Expression; D014644:Genetic Variation; D008221:Lymphoid Tissue / Q000378:metabolism; D008231:Lymphopenia / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D005810:Multigene Family; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011913:Rats, Inbred BB / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution
D017931:DNA Primers; D018076:DNA, Complementary; D012333:RNA, Messenger; D019204:GTP-Binding Proteins; C494977:Gimap5 protein, rat