Arts Syndrome Is Caused by Loss-of-Function Mutations in PRPS1

• Published in: American journal of human genetics Vol. 81; no. 3; pp. 507 - 518
• Main Authors: de Brouwer, Arjan P.M., Williams, Kelly L., Duley, John A., van Kuilenburg, André 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
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.09.2007; University of Chicago Press; Cell Press; American Society of Human Genetics
• Subjects: Ataxia - genetics; Biological and medical sciences; Cell Line; Chromosomes, Human, X - genetics; Clinical trials; Erythrocytes - enzymology; Female; Fibroblasts - enzymology; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetic Linkage; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Hearing Loss - genetics; Humans; Intellectual Disability - genetics; Male; Medical disorders; Medical genetics; Medical sciences; Molecular and cellular biology; Muscle Hypotonia - genetics; Mutation; Mutation, Missense; Optic Atrophies, Hereditary - genetics; Pedigree; Protein Conformation; Purines - biosynthesis; Ribose-Phosphate Pyrophosphokinase - analysis; Ribose-Phosphate Pyrophosphokinase - chemistry; Ribose-Phosphate Pyrophosphokinase - genetics; Syndrome; Human; Loss function; Genetics; Art; Mutation; Syndrome
• ISSN: 0002-9297; 1537-6605
• 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.