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PRPS1
phosphoribosyl pyrophosphate synthetase 1
The PRPS1 gene provides instructions for making phosphoribosyl pyrophosphate synthetase 1, an enzyme critical for nucleotide production and purine salvage pathways. The PRPS1 gene encodes the enzyme phosphoribosyl pyrophosphate synthetase 1, which plays a fundamental role in synthesising nucleotides, the basic building blocks of DNA and RNA.
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 is responsible for producing phosphoribosyl pyrophosphate synthetase 1, an enzyme essential for various metabolic processes within the body. This enzyme facilitates the creation of phosphoribosyl pyrophosphate (PRPP), a key molecule required for the initial stages of nucleotide synthesis. Nucleotides are fundamental components of DNA and RNA, as well as crucial energy-carrying molecules like ATP and GTP.
What the gene does
The enzyme encoded by the PRPS1 gene, phosphoribosyl pyrophosphate synthetase 1 (PRPP synthetase 1), is instrumental in both the de novo synthesis and salvage pathways of nucleotides. It catalyses the formation of phosphoribosyl pyrophosphate (PRPP), which is a precursor for both purine and pyrimidine nucleotides. Purines and pyrimidines are the two main types of nitrogenous bases found in DNA and RNA. Additionally, PRPP synthetase 1 is vital for the purine salvage pathway, a more energy-efficient process that recycles purines from existing DNA and RNA breakdown products, ensuring a continuous supply of these critical molecules for cellular functions.
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Chromosome location
The PRPS1 gene is located on the long arm of the X chromosome at position 22.3, designated as Xq22.3. As an X-linked gene, its inheritance patterns can differ between males and females.
Protein structure
The PRPS1 protein comprises 318 amino acids. A crucial functional region is involved in the binding of phosphoribosylpyrophosphate, located between amino acids 212-227. This binding site is integral to the enzyme's catalytic activity in nucleotide synthesis.
Key variants
Genetic changes, known as pathogenic variants, in the PRPS1 gene can impact its function, leading to a spectrum of health conditions. These variants can alter the enzyme's structure or activity, thereby disrupting crucial metabolic pathways involved in nucleotide synthesis and recycling. The specific clinical presentation often depends on the nature and location of the genetic change.
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 | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.343A>G | p.Met115Val | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease X-linked recessive 5 |
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 | ★★☆☆ | Charcot-Marie-Tooth Neuropathy X |
c.640C>T | p.Arg214Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Retinal dystrophy |
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 its critical role in cellular metabolism. These include Arts syndrome, which primarily affects males and causes severe neurological symptoms. Other conditions linked to PRPS1 variants include phosphoribosylpyrophosphate synthetase superactivity, characterised by uric acid build-up, Charcot-Marie-Tooth disease, and non-syndromic hearing loss.
UK clinical status
The PRPS1 gene is recognised within several UK NHS Genomic Medicine Service national test panels on PanelApp. It is listed as 'green' for conditions such as DDG2P, Hereditary neuropathy, Intellectual disability, Monogenic hearing loss, and Retinal disorders, indicating strong evidence for its involvement in these conditions. It is also listed under 'Hereditary neuropathy or pain disorder' (R78) and 'Likely inborn error of metabolism' (R98), and 'Undiagnosed metabolic disorders', further highlighting its clinical relevance.
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 nucleotides, the building blocks of DNA and RNA, and for the purine salvage pathway.
What conditions are associated with PRPS1 gene variants?
Pathogenic variants in the PRPS1 gene are associated with several conditions, including Arts syndrome, phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease, and non-syndromic hearing loss.
Is the PRPS1 gene located on a sex chromosome?
Yes, the PRPS1 gene is located on the X chromosome, specifically at position Xq22.3. This means it is an X-linked gene.
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