Digenic inheritance of severe insulin resistance in a human pedigree

DB Savage, M Agostini, I Barroso, M Gurnell, J Luan… - Nature …, 2002 - nature.com
DB Savage, M Agostini, I Barroso, M Gurnell, J Luan, A Meirhaeghe, AH Harding, G Ihrke
Nature genetics, 2002nature.com
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
heterozygous with respect to frameshift/premature stop mutations in two unlinked genes …
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 heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor γ, 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.
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