Arts syndrome is caused by loss-of-function mutations in PRPS1

de Brouwer, A. P. M., Williams, K. L., Duley, J. A., van Kuilenburg, A. B. P., Nabuurs, S. B., Egmont-Petersen, M., Lugtenberg, D., Zoetekouw, L., Banning, M. J. G., Roeffen, M., Hamel, B. C. J., Weaving, L., Ouvrier, R. A., Donald, J. A., Wevers, RA, Christodoulou, J. and van Bokhoven, H. (2007) Arts syndrome is caused by loss-of-function mutations in PRPS1. American Journal of Human Genetics, 81 3: 507-518.


Author de Brouwer, A. P. M.
Williams, K. L.
Duley, J. A.
van Kuilenburg, A. B. P.
Nabuurs, S. B.
Egmont-Petersen, M.
Lugtenberg, D.
Zoetekouw, L.
Banning, M. J. G.
Roeffen, M.
Hamel, B. C. J.
Weaving, L.
Ouvrier, R. A.
Donald, J. A.
Wevers, RA
Christodoulou, J.
van Bokhoven, H.
Title Arts syndrome is caused by loss-of-function mutations in PRPS1
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2007
Sub-type Article (original research)
DOI 10.1086/520706
Volume 81
Issue 3
Start page 507
End page 518
Total pages 12
Place of publication Chicago
Publisher Univ Chicago Press
Collection year 2008
Language eng
Subject C1
320000 Medical and Health Sciences
730000 - Health
Abstract Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Linkage analysis in a Dutch family and an Australian family suggested that the candidate gene maps to Xq22.1-q24. Oligonucleotide microarray expression profiling of fibroblasts from two probands of the Dutch family revealed reduced expression levels of the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1). Subsequent sequencing of PRPS1 led to the identification of two different missense mutations, c.455T -> C (p.L152P) in the Dutch family and c.398A -> C (p.Q133P) in the Australian family. Both mutations result in a loss of phosphoribosyl pyrophosphate synthetase 1 activity, as was shown in silico by molecular modeling and was shown in vitro by phosphoribosyl pyrophosphate synthetase activity assays in erythrocytes and fibroblasts from patients. This is in contrast to the gain-of-function mutations in PRPS1 that were identified previously in PRPS-related gout. The loss-of-function mutations of PRPS1 likely result in impaired purine biosynthesis, which is supported by the undetectable hypoxanthine in urine and the reduced uric acid levels in serum from patients. To replenish low levels of purines, treatment with S-adenosylmethionine theoretically could have therapeutic efficacy, and a clinical trial involving the two affected Australian brothers is currently underway.
Keyword Genetics & Heredity
Linked Mental-retardation
Human Phosphoribosylpyrophosphate Synthetase-1
S-adenosylhomocysteine Hydrolase
Nonselective Cation Channels
Uric-acid Overproduction
Pyrophosphate Synthetase
Human-erythrocytes
Purine Metabolism
Adenosine Kinase
Early-childhood
Q-Index Code C1
Q-Index Status Confirmed Code

 
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Created: Mon, 18 Feb 2008, 14:54:50 EST