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Digenic inheritance of severe insulin resistance in a human pedigree

Nature Genetics volume 31, pages 379–384 (2002)Cite this article

An Erratum to this article was published on 01 September 2002

This article has been updated

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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Figure 1: Detection of mutations in PPARG and in PPP1R3A families with severe insulin resistance.
Figure 2: Functional properties of the PPARγ mutant receptors.
Figure 3: Characterization of the PPP1R3A mutant.

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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

  1. 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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Author notes

  1. David B. Savage, Maura Agostini, Inês Barroso, Mark Gurnell and Jian'an Luan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK

    David B. Savage, Aline Meirhaeghe, Gudrun Ihrke, Maria A. Soos, Stella George, Dirk Berger, Antonio Vidal-Puig & Stephen O'Rahilly

  2. Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK

    David B. Savage, Maura Agostini, Mark Gurnell, Aline Meirhaeghe, Odelia Rajanayagam, Maria A. Soos, Stella George, Dirk Berger, Antonio Vidal-Puig, Stephen O'Rahilly & V. Krishna K. Chatterjee

  3. Incyte Genomics, Palo Alto, 3160 Porter Drive, California, USA

    Inês Barroso & Alan J. Schafer

  4. Department of Public Health, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

    Jian'an Luan, Anne-Helen Harding & Nicholas J. Wareham

  5. The Robert Steiner MRI Unit, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK

    E. Louise Thomas & Jimmy D. Bell

  6. Department of Endocrinology, Imperial College Faculty of Medicine, Charing Cross and Hammersmith Hospitals, London, UK

    Karim Meeran

  7. Division of Clinical Sciences, University of Sheffield, Sheffield, UK

    Richard J. Ross

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Corresponding author

Correspondence to Stephen O'Rahilly.

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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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