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

Authors: de Brouwer, Arjan P M  Williams, Kelly L  Duley, John A  van Kuilenburg, AndrĂ© B P  Nabuurs, Sander B  Egmont-Petersen, Michael  Lugtenberg, Dorien  Zoetekouw, Lida  Banning, Martijn J G  Roeffen, Melissa  Hamel, Ben C J  Weaving, Linda  Ouvrier, Robert A  Donald, Jennifer A  Wevers, Ron A  Christodoulou, John  van Bokhoven, Hans 
Citation: de Brouwer AP, etal., Am J Hum Genet. 2007 Sep;81(3):507-18. Epub 2007 Aug 3.
Pubmed: (View Article at PubMed) PMID:17701896
DOI: Full-text: DOI:10.1086/520706

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.

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CRRD Object Information
CRRD ID: 12910562
Created: 2017-06-20
Species: All species
Last Modified: 2017-06-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.