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.
Article first published online: 13 JAN 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 158A, Issue 2, pages 455–460, February 2012
How to Cite
Moran, R., Kuilenburg, A. B.P., Duley, J., Nabuurs, S. B., Retno-Fitri, A., Christodoulou, J., Roelofsen, J., Yntema, H. G., Friedman, N. R., van Bokhoven, H. and de Brouwer, A. P.M. (2012), Phosphoribosylpyrophosphate synthetase superactivity and recurrent infections is caused by a p.Val142Leu mutation in PRS-I. Am. J. Med. Genet., 158A: 455–460. doi: 10.1002/ajmg.a.34428
Rocio Moran and André B.P. Kuilenburg contributed equally to this study.
- Issue published online: 19 JAN 2012
- Article first published online: 13 JAN 2012
- Manuscript Accepted: 16 NOV 2011
- Manuscript Received: 8 APR 2011
- EU 7th Framework Program. Grant Number: 241995 (GENCODYS)
- Dutch Brain Foundation. Grant Number: 2009(2)-81
- Dutch Organization for Health Research and Development (ZON-MW). Grant Number: 917-86-319
- Netherlands Organization for Scientific Research (NWO; VENI). Grant Number: 700.58.410
- Arts syndrome;
- recurrent infections
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.