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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes

Author

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  • Eusebio Chiefari

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Stefania Iiritano

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Francesco Paonessa

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Ilaria Le Pera

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Biagio Arcidiacono

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Mirella Filocamo

    (Laboratorio Diagnosi Pre-Postnatale Malattie Metaboliche, Istituto G. Gaslini, Largo G. Gaslini 5)

  • Daniela Foti

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

  • Stephen A. Liebhaber

    (University of Pennsylvania School of Medicine, 415 Curie Blvd, Philadelphia, Pennsylvania 19104, USA.)

  • Antonio Brunetti

    (Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto)
    Cattedra di Endocrinologia, Università di Catanzaro 'Magna Græcia', viale Europa (Loc. Germaneto))

Abstract

Processed pseudogenes are non-functional copies of normal genes that arise by a process of mRNA retrotransposition. The human genome contains thousands of pseudogenes; however, knowledge regarding their biological role is limited. Previously, we demonstrated that high mobility group A1 (HMGA1) protein regulates the insulin receptor (INSR) gene and that two diabetic patients demonstrated a marked destabilization of HMGA1 mRNA. In this paper we report that this destabilization of HMGA1 mRNA is triggered by enhanced expression of RNA from an HMGA1 pseudogene, HMGA1-p. Targeted knockdown of HMGA1-p mRNA in patient cells results in a reciprocal increase in HMGA1 mRNA stability and expression levels with a parallel correction in cell-surface INSR expression and insulin binding. These data provide evidence for a regulatory role of an expressed pseudogene in humans and establishes a novel mechanistic linkage between pseudogene HMGA1-p expression and type 2 diabetes mellitus.

Suggested Citation

  • Eusebio Chiefari & Stefania Iiritano & Francesco Paonessa & Ilaria Le Pera & Biagio Arcidiacono & Mirella Filocamo & Daniela Foti & Stephen A. Liebhaber & Antonio Brunetti, 2010. "Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes," Nature Communications, Nature, vol. 1(1), pages 1-7, December.
    • Handle: RePEc:nat:natcom:v:1:y:2010:i:1:d:10.1038_ncomms1040
    DOI: 10.1038/ncomms1040
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    Cited by:

    1. Aida Bianco & Eusebio Chiefari & Carmelo G A Nobile & Daniela Foti & Maria Pavia & Antonio Brunetti, 2015. "The Association between HMGA1 rs146052672 Variant and Type 2 Diabetes: A Transethnic Meta-Analysis," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-15, August.

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