This report describes Arts syndrome, which shows X-linked recessive inheritance. The human gene implicated in this disease is PRPS1, phosphoribosylpyrophosphate synthetase 1 (EC 126.96.36.199). Other disorders have been associated with mutations in PRPS1, including a type of Charcot-Marie-Tooth disease (OMIM:311070), X-linked deafness (OMIM:304500), and PRPS-related gout(OMIM:300661).
There is a single high-ranking ortholog of PRPS1 and its paralog PRPS2 in Drosophila, Prps. Several alleles have been generated for Prps, including RNAi targeting constructs and misexpression element insertions.
The human gene Hsap\PRPS1 has been introduced into flies, but has not yet been characterized.
Two alleles have been generated by CRISPR to carry mutations in Prps analogous to those seen in Arts syndrome patients. These mutants are viable, but enzymatic function of Prps is compromised, resulting in a shorter lifespan. When starved, both mutants fail to mobilize stored lipids, and die two days earlier than controls. These phenotypes are caused by defects in lipid mobilization, autophagy induction, lysosome function, and the cellular response to reactive oxygen species. Depletion of Prps in the brain results in an increase in ubiquitinated and aggregated proteins, indicating that the defects in autophagy and protein turnover affect the fly nervous system.
Variant(s) implicated in human disease tested (as analogous mutation in fly gene): Q165P in the fly Prps gene (corresponds to Q133P in the human PRPS1 gene); R228W in the fly Prps gene (corresponds to R196W in the human PRPS1 gene).
[updated Mar. 2020 by FlyBase; FBrf0222196]
[ARTS SYNDROME; ARTS](https://omim.org/entry/301835)
[PHOSPHORIBOSYLPYROPHOSPHATE SYNTHETASE I; PRPS1](https://omim.org/entry/311850)
Arts syndrome is the most severe form of PRPS1 disease, and is characterized by infant death, sensorineural hearing loss, intellectual disability, hypotonia, and ataxia. (Delos Santos et al. 2019, FBrf0243527.)
Arts syndrome is defined by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Susceptibility to infections, especially of the upper respiratory tract, can result in an early death. Interestingly, Arts syndrome shows characteristics in common with purine-overproduction disorders, such as mental retardation, delayed motor development, ataxia, sensorineural impairment, and recurrent infections - symptoms that occur in patients with hypoxanthine guanine phosphoribosyltransferase (HPRT1) deficiency, purine nucleoside phosphorylase (PNP) deficiency, and PRPP synthetase superactivity. However, Arts syndrome lacks evidence of purine overproduction, since patients do not develop renal stones or gout (authors' unpublished observations). (de Brouwer et al. 2007 and references therein, pubmed:17701896.)
Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy (de Brouwer et al. 2007, pubmed:17701896). Susceptibility to infections, especially of the upper respiratory tract, can result in early death. [from OMIM:301835, 2019.10.29]
PRPS1 mutations were identified in a number of X-linked neurological disorders: Arts syndrome, Charcot-Marie-Tooth disease (CMT), and nonsyndromic sensorineural deafness. All PRPS1 mutations identified from patients are missense mutations affecting enzymatic activity to varying degrees. (Delos Santos et al. 2019, FBrf0243527.)
Using linkage analysis, Kremer et al. 1996 (pubmed:8882866) localized the gene (or genes) responsible for the Arts syndrome phenotype to Xq21.33-q24 between DXS1231 and DXS1001 with a maximum LOD score of 6.97. Using oligonucleotide microarray expression profiling in fibroblasts from 2 probands of a Dutch family with Arts syndrome, de Brouwer et al. 2007 (pubmed:17701896) found reduced expression levels of the PRPS1 gene. [from OMIM:301835, 2019.10.29]
The loss-of-function mutations of PRPS1 described by de Brouwer et al. 2007 (pubmed:17701896) 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. [adapted from OMIM:301835, 2019.10.29]
Phosphoribosyl pyrophosphate synthetase (PRPS) is a rate-limiting enzyme in the biosynthesis of purine, pyrimidine, and, pyridine nucleotides. PRPS produces phosphoribosyl pyrophosphate (PRPP), a common precursor of the five-carbon sugar subunit of nucleotides. (Delos Santos et al. 2019, FBrf0243527.)