PUS1
protein-codingpseudouridine synthase 1, the group of Pseudouridine synthases
Gene summary
This gene encodes a pseudouridine synthase that converts uridine to pseudouridine once it has been incorporated into an RNA molecule. The encoded enzyme may play an essential role in tRNA function and in stabilizing the secondary and tertiary structure of many RNAs. A mutation in this gene has been linked to mitochondrial myopathy and sideroblastic anemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0024553
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0024553
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0024553
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0024553
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0000863
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *PUS1* and autosomal recessive primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 1, 2022. The *PUS1* gene encodes pseudouridine synthase 1, which functions in mitochondrial transcript processing and modification. The *PUS1* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2004 (PMID: 15108122) when the molecular defects in families whose phenotype was described as a new syndrome of myopathy, lactic acidosis, and sideroblastic anemia (MLASA) in 1995 (PMID: 7726239) were identified. While various names have been given to the constellation of features seen in those with *PUS1*-related disease, including autosomal recessive MLASA (MIM 600462), pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *PUS1* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five unique variants (four stop-gained variants, one frameshift variant, and one missense variant) identified in five individuals from five publications (PMIDs: 15108122, 17056637, 19731322, 25058219, 26556812). Additional evidence is available in the literature (PMIDs: 15971356, 28832011, 25227147), but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of disease appears to be loss of function. The c.885C>T (p.Arg144Trp) variant is recognized as a founder variant in the Middle Eastern Jewish population. This gene-disease relationship is also supported by a biochemical function (mitochondrial RNA processing for translation) shared with other genes associated with primary mitochondrial disease and recapitulation of the myopathy and mitochondrial dysfunction in muscle observed in human patients in a knockout mouse model (PMID: 27197761). In summary, there is definitive evidence to support the relationship between *PUS1* and autosomal recessive primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 1, 2022 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0024553
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Hematologic; Musculoskeletal; Neurologic
Intervention: Hematologic
Rationale: Severe, non-B6 responsive anemia has reportedly required transfusions
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PUS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_025215.6. 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 | 1 | 298 | 1 | 300 | ||
| missense | 6 | 168 | 16 | 190 | ||
| nonsense | 12 | 12 | 24 | |||
| start loss | 3 | 3 | ||||
| frameshift | 27 | 27 | 54 | |||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 39 | 56 | 169 | 314 | 1 | 579 |
Highest pathogenic variant AF is 0.000055407727
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_079491.2 | 6 | MANE Select | |
| Ensembl | ENSP00000365837.3 | 6 | MANE Select | |
| RefSeq | NP_001002019.1 | 5 | Standard | |
| RefSeq | NP_001002020.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- tRNA modification in the nucleus and cytosol
- tRNA processing
- tRNA modification in the mitochondrion
- Metabolism of RNA
- Pyrimidine metabolism
Biological Process
- tRNA pseudouridine synthesis
- mitochondrial tRNA pseudouridine synthesis
- mRNA pseudouridine synthesis
Molecular Function
- tRNA binding
- steroid receptor RNA activator RNA binding
- RNA binding
- pseudouridine synthase activity
- tRNA pseudouridine synthase activity
Cellular Component
- nucleus
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000376649
- Coding exons
- 6
- Length
- 14662
- Individuals with no LoFs
- 125729
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 125741
- p
- 0.0000477
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.291 | 250 | 263 | 0.949 | 0.0000171 | 2758 |
| Missense (PolyPhen) | 85 | 106.14 | 0.80084 | 1133 | ||
| Synonymous | -0.154 | 123 | 121 | 1.02 | 0.00000867 | 861 |
| Loss of Function | 1.98 | 7 | 15.4 | 0.455 | 6.57e-7 | 193 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Converts specific uridines to PSI in a number of tRNA substrates. Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA. Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 RNA. {ECO:0000269|PubMed:24722331}.;
Recessive Scores
- pRec
- 0.134
Intolerance Scores
- LoFtool
- 0.684
- RVIS EVS
- -0.75
- RVIS percentile EVS
- 13.58
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.940
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |