title: Arts syndrome is caused by loss-of-function mutations in PRPS1.
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.
authors: Departments of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. A.debrouwer@antrg.umcn.nl
authors: Arjan P M
authors: AP
authors: de Brouwer
authors: Kelly L
authors: KL
authors: Williams
authors: John A
authors: JA
authors: Duley
authors: André B P
authors: AB
authors: van Kuilenburg
authors: Sander B
authors: SB
authors: Nabuurs
authors: Michael
authors: M
authors: Egmont-Petersen
authors: Dorien
authors: D
authors: Lugtenberg
authors: Lida
authors: L
authors: Zoetekouw
authors: Martijn J G
authors: MJ
authors: Banning
authors: Melissa
authors: M
authors: Roeffen
authors: Ben C J
authors: BC
authors: Hamel
authors: Linda
authors: L
authors: Weaving
authors: Robert A
authors: RA
authors: Ouvrier
authors: Jennifer A
authors: JA
authors: Donald
authors: Ron A
authors: RA
authors: Wevers
authors: John
authors: J
authors: Christodoulou
authors: Hans
authors: H
authors: van Bokhoven
mesh_terms: D001259:Ataxia / Q000235:genetics*; D002460:Cell Line; D041321:Chromosomes, Human, X / Q000235:genetics; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D008040:Genetic Linkage; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics*; D020125:Mutation, Missense; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D010375:Pedigree; D011487:Protein Conformation; D011687:Purines / Q000096:biosynthesis; D012268:Ribose-Phosphate Pyrophosphokinase / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome
chemical_list: D011687:Purines; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase
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