Is mortalin a candidate gene for T1DM ?
Mortalin has been found to be up-regulated by 2D-protein gel analysis in isolated rodent islets exposed to cytokines. In islets from two rat strains with different sensitivity to the toxic effects of cytokines we observed a significant difference in IL-1beta mediated mortalin expression. Constitutive over-expression of rat mortalin in NIH3T3 cells reduced cellular survival in accordance with mortalin being associated to cellular senescence. Hence we consider the gene encoding for mortalin at chromosome 5q31.1 a putative candidate gene in cytokine induced beta-cell destruction. We scanned the human mortalin gene for polymorphisms and identified three novel polymorphisms. Neither the SNPs individually nor as constructed haplotypes showed disease association tested by (E)TDT in a Danish type 1 diabetes (T1DM) population. Furthermore, we tested the D5S500 microsatelite located close to 5q31.1 without finding linkage to (T1DM). In conclusion, the functional data identifying a difference in mortalin expression in IL-1beta stimulated islets between two rat strains and over-expression of mortalin in NIH3T3 cells associated with decreased viability suggests a functional role for mortalin in cytokine mediated beta cell destruction; however, the identified polymorphisms did not reveal any association in the presence of linkage disequilibrium of mortalin to T1DM in the Danish population.
Johannesen
Jesper
J
Steno Diabetes Center, Niels Steensens Vej, Gentofte, Denmark.
Pie
Angeles
A
Karlsen
Allan Ertmann
AE
Larsen
Zenia Marian
ZM
Jensen
Allan
A
Vissing
Henrik
H
Kristiansen
Ole Peter
OP
Pociot
Flemming
F
Nerup
Jørn
J
D000818:Animals; D003001:Cloning, Molecular; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D018014:Gene Transfer Techniques; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D051381:Rats; D011914:Rats, Inbred BN
D018840:HSP70 Heat-Shock Proteins; C080352:mortalin