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PRPS1
phosphoribosyl pyrophosphate synthetase 1
The PRPS1 gene provides instructions for making phosphoribosyl pyrophosphate synthetase 1, an enzyme critical for synthesising and recycling nucleotides, the fundamental building blocks of DNA and RNA. The PRPS1 gene encodes the enzyme phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1, which is essential for producing phosphoribosyl pyrophosphate (PRPP).
PRPS1 is located on the long (q) arm of chromosome X, at band Xq22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The PRPS1 gene, located on the X chromosome, is responsible for producing phosphoribosyl pyrophosphate synthetase 1, an enzyme critical for cell metabolism. This enzyme is involved in the synthesis of nucleotides, which are fundamental components of DNA and RNA, as well as energy-carrying molecules like ATP and GTP. Its proper function is vital for maintaining cellular health and various physiological processes.
What the gene does
The PRPS1 gene encodes the enzyme phosphoribosyl pyrophosphate synthetase 1 (PRPP synthetase 1), which catalyses the production of phosphoribosyl pyrophosphate (PRPP). PRPP is a crucial molecule involved in the initial steps of nucleotide synthesis, both for purines and pyrimidines. Furthermore, PRPP and PRPP synthetase 1 are indispensable for the purine salvage pathway, a more energy-efficient process that recycles purines and pyrimidines from the breakdown of DNA and RNA. This recycling mechanism ensures a continuous and adequate supply of nucleotides for cell growth, repair, and energy metabolism [PMID:24810862]. PRPP is also vital for the formation of purines and pyrimidines de novo, meaning synthesised from smaller precursor molecules [PMID:24810862].
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Chromosome location
The PRPS1 gene is situated on the long arm of the X chromosome at position 22.3, designated as Xq22.3. This chromosomal location is significant, as X-linked inheritance patterns can lead to differing impacts between males and females.
Protein structure
The PRPS1 gene encodes a protein that is 318 amino acids in length. This protein contains a specific functional region important for its enzymatic activity: the binding of phosphoribosylpyrophosphate, located between amino acids 212 and 227. This region is crucial for the enzyme to interact with its substrate and catalyse the production of PRPP.
Key variants
Variants within the PRPS1 gene can impact the structure and function of the encoded enzyme, phosphoribosyl pyrophosphate synthetase 1. These genetic changes can lead to a range of clinical presentations, depending on the specific alteration and its effect on enzyme activity. Some variants may result in reduced enzyme function, while others can cause increased activity or alter protein stability.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.250C>T | p.Arg84Trp | Pathogenic/Likely pathogenic | ★★☆☆ | PRPS1-related disorder |
c.343A>G | p.Met115Val | Pathogenic/Likely pathogenic | ★★☆☆ | Hearing loss, X-linked 1 |
c.344T>C | p.Met115Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.506C>T | p.Ser169Leu | Pathogenic | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.586C>T | p.Arg196Trp | Pathogenic/Likely pathogenic | ★★☆☆ | PRPS1-related disorder |
c.640C>T | p.Arg214Trp | Pathogenic/Likely pathogenic | ★★☆☆ | PRPS1-related disorder |
c.307-2A>G | - | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.462G>A | p.Trp154Ter | Pathogenic | ★☆☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.570del | p.Ala190_Leu191insTer | Pathogenic | ★☆☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.621del | p.Val208fs | Pathogenic | ★☆☆☆ | Charcot-Marie-Tooth Neuropathy X |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the PRPS1 gene are associated with several inherited conditions, reflecting the enzyme's central role in nucleotide metabolism. These include Arts syndrome, a disorder that primarily affects males with serious neurological problems. Other conditions linked to PRPS1 variants include phosphoribosylpyrophosphate synthetase superactivity, leading to excess uric acid, and some forms of Charcot-Marie-Tooth disease and nonsyndromic hearing loss.
UK clinical status
The PRPS1 gene is recognised within the NHS Genomic Medicine Service, being listed on several green-rated PanelApp panels. These include 'DDG2P', 'Hereditary neuropathy', 'Hereditary neuropathy or pain disorder (R78)', 'Intellectual disability', 'Likely inborn error of metabolism (R98)', 'Monogenic hearing loss (R67)', 'Retinal disorders (R32)', and 'Undiagnosed metabolic disorders'.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PRPS1 gene?
The PRPS1 gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1, which is crucial for producing phosphoribosyl pyrophosphate (PRPP). PRPP is essential for creating new nucleotides and for recycling existing ones, which are the building blocks of DNA and RNA [PMID:24810862].
What is Arts syndrome?
Arts syndrome is a severe neurological disorder caused by pathogenic variants in the PRPS1 gene. It primarily affects boys and men, who typically experience serious neurological problems. Girls and women can also be affected, but symptoms are generally milder.
Can PRPS1 variants cause conditions other than Arts syndrome?
Yes, in addition to Arts syndrome, variants in the PRPS1 gene can lead to conditions such as phosphoribosylpyrophosphate synthetase superactivity, which results in elevated uric acid levels and can cause kidney stones and gout. It can also be associated with certain forms of Charcot-Marie-Tooth disease and nonsyndromic hearing loss.
References
- Zheng M, Ma JW. Research progress in the genetics of hyperuricaemia and gout. Yi chuan = Hereditas. 2016. PMID: 27103454
- Mittal R, Patel K, Mittal J. Association of PRPS1 Mutations with Disease Phenotypes. Disease markers. 2015. PMID: 26089585
- Liu XZ, Xie D, Yuan HJ. Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy. International journal of audiology. 2013. PMID: 23190330
- de Brouwer AP, van Bokhoven H, Nabuurs SB. PRPS1 mutations: four distinct syndromes and potential treatment. American journal of human genetics. 2010. PMID: 20380929
- de Brouwer AP, Williams KL, Duley JA. Arts syndrome is caused by loss-of-function mutations in PRPS1. American journal of human genetics. 2007. PMID: 17701896
- Kim HJ, Sohn KM, Shy ME. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). American journal of human genetics. 2007. PMID: 17701900
- Nyhan WL. Disorders of purine and pyrimidine metabolism. Molecular genetics and metabolism. 2005. PMID: 16176880
- Adam MP, Bick S, Mirzaa GM. Phosphoribosylpyrophosphate Synthetase Superactivity. 1993. PMID: 20301734
- Adam MP, Bick S, Mirzaa GM. Phosphoribosylpyrophosphate Synthetase Deficiency. 1993. PMID: 20301738