Digenic inheritance of severe insulin resistance in a human pedigree |
| |
Authors: | Savage David B Agostini Maura Barroso Inês Gurnell Mark Luan Jian'an Meirhaeghe Aline Harding Anne-Helen Ihrke Gudrun Rajanayagam Odelia Soos Maria A George Stella Berger Dirk Thomas E Louise Bell Jimmy D Meeran Karim Ross Richard J Vidal-Puig Antonio Wareham Nicholas J O'Rahilly Stephen Chatterjee V Krishna K Schafer Alan J |
| |
Affiliation: | Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK. |
| |
Abstract: | Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|