Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I

Authors

  • Rocio Moran,

    1. Cleveland Clinic Foundation, Genomic Medicine Institute, Cleveland, Ohio
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  • André B.P. Kuilenburg,

    1. Emma Children's Hospital and Division of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • John Duley,

    1. School of Pharmacy, The University of Queensland, Brisbane, Australia
    2. Department of Pathology, Mater Hospital, Brisbane, Australia
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  • Sander B. Nabuurs,

    1. Centre for Molecular and Biomolecular Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands
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  • Aditia Retno-Fitri,

    1. Department of Human Genetics, Institute of Genetic and Metabolic Disease, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • John Christodoulou,

    1. Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, and Disciplines of Paediatrics and Child Health and Genetic Medicine, University of Sydney, Sydney, Australia
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  • Jeroen Roelofsen,

    1. Emma Children's Hospital and Division of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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  • Helger G. Yntema,

    1. Department of Human Genetics, Institute of Genetic and Metabolic Disease, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Neil R. Friedman,

    1. Cleveland Clinic Foundation, Neurological Institute, Cleveland, Ohio
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  • Hans van Bokhoven,

    1. Department of Human Genetics, Institute of Genetic and Metabolic Disease, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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  • Arjan P.M. de Brouwer

    Corresponding author
    1. Department of Human Genetics, Institute of Genetic and Metabolic Disease, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
    • Department of Human Genetics—855, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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  • How to Cite this Article: Moran R, Kuilenburg ABP, Duley J, Nabuurs SB, Retno-Fitri A, Christodoulou J, Roelofsen J, Yntema HG, Friedman NR, van Bokhoven H, de Brouwer APM. 2012. Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. Am J Med Genet Part A 158A:455–460.

  • Rocio Moran and André B.P. Kuilenburg contributed equally to this study.

Abstract

We identified a novel missense mutation, c.424G>C (p.Val142Leu) in PRPS1 in a patient with uric acid overproduction without gout but with developmental delay, hypotonia, hearing loss, and recurrent respiratory infections. The uric acid overproduction accompanying this combination of symptoms suggests that the patient presented with phosphoribosylpyrophosphate (PRPP) synthetase superactivity, but recurrent infections have not been associated with superactivity until now. However, recurrent infections are a prominent feature of patients with Arts syndrome, which is caused by PRPS1 loss-of-function mutations, indicating that the patient reported here has an intermediate phenotype. Molecular modeling predicts that the p.Val142Leu change affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss-of-function of PRPP synthetase. This finding is in line with the normal PRPP synthetase activity in fibroblasts and the absence of activity in erythrocytes of the present patient. We postulate that the overall effect of the p.Val142Leu change on protein activity is determined by the cell type, being a gain-of-function in proliferating cells and a loss-of-function in postmitotic cells. Our results show that missense mutations in PRPS1 can cause a continuous spectrum of features ranging from progressive non-syndromic postlingual hearing impairment to uric acid overproduction, neuropathy, and recurrent infections depending on the functional sites that are affected. © 2012 Wiley Periodicals, Inc.

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