PRPS1
protein-codingphosphoribosyl pyrophosphate synthetase 1
Gene summary
This gene encodes an enzyme that catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for purine metabolism and nucleotide biosynthesis. Defects in this gene are a cause of phosphoribosylpyrophosphate synthetase superactivity, Charcot-Marie-Tooth disease X-linked recessive type 5 and Arts Syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]
- DFN2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~23.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0018464
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0018495
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010533
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0100061
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0100061
Submitter: ClinGen
The PRPS1 gene has been associated with X-linked syndromic and non-syndromic hearing loss in at least 14 probands across 13 publications. Fourteen unique loss of function (LOF) missense variants have been reported in humans. Variants in this gene segregated with disease in more than 15 additional family members. PRPS1 was first associated with hearing loss in humans in 1988 (Becker et al.); however, since then LOF variants in this gene have also been associated with syndromic conditions in which hearing loss is a feature, including Charcot-Marie-Tooth disease (CMTX5), Arts Syndrome, and more severe deficiency disorders. Of note, intellectual disability and developmental delay are usually associated with Arts syndrome and more severe cases of PRPS1 deficiency, but not CMTX5 or nonsyndromic hearing loss (PMID: 24961627). While most males with Arts syndrome present with mild to moderate intellectual disability, females may have milder phenotypes. Additionally, visual and hearing impairment can make it difficult to assess cognitive ability. Because these conditions exist on a spectrum of severity, there may be significant overlap between phenotypes. There is some understanding of the mechanisms by which missense variants cause each disorder using structural analysis and crystal structures of the protein and its variants, but intrafamilial phenotypic variation makes it difficult to separate PRPS1 nonsyndromic and syndromic hearing loss. Loss of function variants have been found to cause nonsyndromic hearing loss, CMTX5 and Arts Syndrome, while PRPS1 superactivity disorders, which have been assessed separately, are caused by gain of function variants that destabilize allosteric sites (de Brouwer et al. 2010). In summary, PRPS1 is definitively associated with syndromic and nonsyndromic X-linked sensorineural hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This curation was originally approved by the ClinGen Hearing Loss gene curation expert panel (GCEP) on 7/9/2018. The ClinGen ID/Autism GCEP reviewed the curation on 12/11/2019 to include additional information about the incidence of intellectual disability in the disease spectrum.
Inheritance Pattern: XL
Disease ID:MONDO:0010395
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010395
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010699
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010577
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010533
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010533
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010395
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XLR
Disease ID:MONDO:0010395
Submitter: Natera
Inheritance Pattern: XLR
Disease ID:MONDO:0100061
Submitter: Natera
Inheritance Pattern: XL
Disease ID:MONDO:0018463
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010699
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010395
Submitter: ClinGen
The PRPS1 gene has been associated with X-linked phosphoribosylpyrophosphate synthetase superactivity using the ClinGen Clinical Validity Framework as of 7/5/2018. This association was made using case-level and experimental data. At least 9 unique gain of function (GOF) missense variants have been reported in humans. The PRPP protein was first associated with this disease in humans as early as 1972 (Sperling et al.); however, Roessler et al. first identified variants in the PRPS1 gene in 1993. Association is seen in at least 8 probands across 5 publications (PMID: 7593598, 28742244, 22246954, 8253776, 12847698). Variants in this gene segregated with disease in 1 additional family member (PMID: 28742244). The crystal structure of this enzyme has been solved, which informs that functionally assessed GOF missense variants are located in one of two allosteric sites in the protein (Chen et al. 2015). This gene-disease association is supported by functional assays demonstrating that PRPS1 variants cause an overproduction of pyrimidines, leading to hyperuricemia and gout (PMID: 7593598, 28742244, 23509005). Of note, intellectual disability and developmental delay are present in the severe superactivity phenotype, which is usually observed in infants or young children; in contrast, the mild phenotype normally lacks these conditions and manifests in juvenile or adult probands (PMID: 22246954, 28742244). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanisms between GOF missense variants in PRPS1-superactivity and PRPS1 deficiency disorders (X-linked nonsyndromic hearing loss, Charcot-Marie-Tooth disease, Arts syndrome, and more severe deficiency phenotypes), which are caused by loss of function missense variants. In summary, there is limited evidence to support this gene-disease association. Although additional case-level information is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease association. These classifications were approved by the ClinGen Hearing Loss Working Group on 7/9/2018. The ClinGen ID/Autism GCEP reviewed the curation on 12/11/2019 to include additional information about the incidence of intellectual disability in the disease spectrum.
Inheritance Pattern: XL
Disease ID:MONDO:0100061
Submitter: Illumina
Inheritance Pattern: XL
Disease ID:MONDO:0019586
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Hematologic; Neurologic; Renal
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Biochemical; Renal
Rationale: In Arts syndrome, treatment with S-adenosylmethionine may be beneficial, and due to infectious risk, prophylaxis and early and aggressive treatment of infections may decrease related morbidity and mortality; Several PRPS1-related conditions can include deafness, which can be congenital/prelingual, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In Phosphoribosylpyrophosphate synthetase I superactivity, medical treatment of uric acid overproduction can be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PRPS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002764.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 109 | 1 | 117 | ||
| missense | 14 | 36 | 140 | 1 | 191 | |
| nonsense | 1 | 4 | 5 | |||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 5 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 18 | 20 | ||
| Total | 19 | 37 | 171 | 110 | 1 | 338 |
Highest pathogenic variant AF is 9.1079573e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002755.1 | 7 | MANE Select | |
| Ensembl | ENSP00000361512.4 | 7 | MANE Select | |
| RefSeq | NP_001191331.1 | 3 | Standard | |
| Ensembl | ENSP00000361495.2 | 6 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| prps1a | Danio rerio | Structure: neuromast hair cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Purine metabolism - Homo sapiens (human)
- Pentose phosphate pathway - Homo sapiens (human)
- Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
- Nucleotide Metabolism
- Pentose phosphate pathway (hexose monophosphate shunt)
Biological Process
- 5-phosphoribose 1-diphosphate biosynthetic process
- purine nucleobase metabolic process
- purine nucleotide biosynthetic process
- pyrimidine nucleotide biosynthetic process
- nervous system development
Molecular Function
- magnesium ion binding
- ribose phosphate diphosphokinase activity
- protein binding
- ATP binding
- kinase activity
Cellular Component
- ribose phosphate diphosphokinase complex
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000372435
- Coding exons
- 7
- Length
- 22520
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.73 | 10 | 130 | 0.0772 | 0.00000998 | 2113 |
| Missense (PolyPhen) | 0 | 34.661 | 0 | 573 | ||
| Synonymous | 0.481 | 41 | 45.1 | 0.909 | 0.00000335 | 621 |
| Loss of Function | 2.61 | 0 | 7.94 | 0.00 | 5.01e-7 | 158 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis.;
- Disease
- DISEASE: Note=Phosphoribosyl pyrophosphate synthetase I deficiency is a rare condition caused by mutations in PRPS1 that lead to variable disease phenotypes including optic atrophy, retinitis pigmentosa, ataxia, peripheral neuropathy and hearing loss. {ECO:0000269|PubMed:25491489}.; DISEASE: Phosphoribosylpyrophosphate synthetase superactivity (PRPS1 superactivity) [MIM:300661]: Familial disorder characterized by excessive purine production, gout and uric acid urolithiasis. {ECO:0000269|PubMed:7593598, ECO:0000269|Ref.12}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, X-linked recessive, 5 (CMTX5) [MIM:311070]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. {ECO:0000269|PubMed:17701900}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: ARTS syndrome (ARTS) [MIM:301835]: A disorder characterized 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 early death. {ECO:0000269|PubMed:17701896}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, X-linked, 1 (DFNX1) [MIM:304500]: A form of deafness characterized by progressive, severe-to-profound sensorineural hearing loss in males. Females manifest mild to moderate hearing loss. {ECO:0000269|PubMed:20021999}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A mutation in PRPS1 has been found in a patient with a phenotype that bridges that of PRSPS1 superactivity and ARTS syndrome with uric acid overproduction without gout but with recurrent infections, sensorineural hearing loss and motor neuropathy. The intermediate phenotype may be because Leu-142 variant affects both allosteric sites that are involved in inhibition of PRPS1 and the ATP-binding site, which suggests that this substitution can result both in a gain-of-function and loss- of-function of PRPP synthetase. {ECO:0000269|PubMed:22246954}.;
Recessive Scores
- pRec
- 0.292
Intolerance Scores
- RVIS EVS
- 0.04
- RVIS percentile EVS
- 56.25
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.947