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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Change history
12 August 2002
The word 'compound' was changed to 'doubly'; the full text was updated, the pdf was appended with a note. An erratum will be published in the September issue.
Notes
NOTE: Owing to a copy-editing error that was implemented after the authors returned the corrected proofs, the term 'doubly heterozygous' was substituted with the term 'compound heterozygous' throughout the text and in Table 1. Similarly, 'double heterozygotes' was erroneously substituted with 'compound heterozygotes'. The full text of the online version of the Letter, including Table 1, has been corrected. Per company policy, the PDF version has not been corrected; an erratum will be published in an upcoming issue. Nature Genetics sincerely regrets these errors.
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Acknowledgements
This study drew upon the combined efforts of many individuals at Incyte Genomics Cambridge, to whom we extend our appreciation. We thank the patients and their families who participated in this study, P. Luzio for helpful discussion, V. Ibbotson for assistance with clinical investigations, K. Ong for HOMA analysis and I. Halsall for insulin and leptin measurements. D.B.S. is a Wellcome Trust Training Fellow, and S.O'R. and V.K.K.C. are supported by the Wellcome Trust. A.M. is funded by an Individual Marie Curie Fellowship. N.J.W., A.H.H., E.L.T. and J.D.B. are supported by the Medical Research Council.
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Savage, D., Agostini, M., Barroso, I. et al. Digenic inheritance of severe insulin resistance in a human pedigree. Nat Genet 31, 379–384 (2002). https://doi.org/10.1038/ng926
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DOI: https://doi.org/10.1038/ng926
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