| First Author | Berchtold LA | Year | 2011 |
| Journal | Proc Natl Acad Sci U S A | Volume | 108 |
| Issue | 37 | Pages | E681-8 |
| PubMed ID | 21705657 | Mgi Jnum | J:176265 |
| Mgi Id | MGI:5289771 | Doi | 10.1073/pnas.1104384108 |
| Citation | Berchtold LA, et al. (2011) Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and {beta}-cell apoptosis. Proc Natl Acad Sci U S A 108(37):E681-8 |
| abstractText | Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting beta-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease-causing genes in T1D, we performed an in silico 'phenome-interactome analysis' on a genome-wide linkage scan dataset. This method prioritizes candidates according to their physical interactions at the protein level with other proteins involved in diabetes. A total of 11 genes were predicted to be likely disease genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi knockdown experiments established that HIP14 is an antiapoptotic protein required for beta-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1beta and IFN-gamma) that mediate beta-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated rat and human islets. Overexpression of HIP14 was associated with a decrease in IL-1beta-induced NF-kappaB activity and protection against IL-1beta-mediated apoptosis. Our study demonstrates that the current network biology approach is a valid method to identify genes of importance for T1D and may therefore embody the basis for more rational and targeted therapeutic approaches. |
