On this page
PUS1
pseudouridine synthase 1
PUS1 is located on the long (q) arm of chromosome 12, at band 12q24.33. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 12 in the library →Available at Jeen Health
Clinical tests that include this
Overview
PUS1 encodes pseudouridine synthase 1, a highly conserved enzyme responsible for converting uridine residues to pseudouridine in transfer RNA (tRNA) and other cellular RNA molecules. This modification process, termed pseudouridylation, is one of the most abundant RNA modifications in living cells and plays a fundamental role in maintaining proper RNA structure and function.
Pathogenic variants in PUS1 are associated with mitochondrial myopathy, lactic acidosis, and sideroblastic anaemia (MLASA), a rare inherited disorder affecting multiple organ systems. The gene is recognised across several NHS Genomic Medicine Service panels for mitochondrial disorders, congenital anaemias, and inborn errors of metabolism, reflecting its importance in cellular energy production and haematopoiesis.
What the gene does
The PUS1 protein functions as a pseudouridine synthase, catalysing the isomerisation of specific uridine residues to pseudouridine within transfer RNA molecules. This enzymatic activity is essential for stabilising RNA secondary structure and ensuring accurate protein translation. The enzyme recognises particular sequence motifs within tRNA substrates and modifies them at specific positions, thereby influencing how efficiently ribosomes decode genetic information.
Pseudouridine differs from uridine by an altered chemical bond that provides additional hydrogen-bonding capacity, which strengthens RNA folding and enhances resistance to degradation. PUS1 activity is particularly important in mitochondria, where it modifies mitochondrial tRNA molecules essential for synthesising components of the electron transport chain. Disruption of this modification process impairs mitochondrial protein synthesis, compromising cellular energy production and leading to the accumulation of metabolic intermediates such as lactate.
Video: Genetics 101
Chromosome location
PUS1 is located on chromosome 12 at position q24.33, within the long arm of the chromosome. The gene spans a region containing multiple exons that together encode the full-length protein. This chromosomal region has been associated with various metabolic and mitochondrial phenotypes in genetic mapping studies.
Protein structure
The PUS1 protein comprises 427 amino acids and contains distinct structural features that facilitate its catalytic function. The protein includes two disordered regions: one spanning amino acids 20-83 near the N-terminus, and another at the C-terminal end from amino acids 407-427. These disordered regions likely provide flexibility for substrate recognition and binding, allowing the enzyme to interact with diverse tRNA molecules. The central catalytic core of the protein contains the conserved domains responsible for pseudouridylation activity, enabling the enzyme to perform its RNA modification function across both cytoplasmic and mitochondrial compartments.
Key variants
Pathogenic variants in PUS1 typically result in reduced or absent enzyme activity, impairing the pseudouridylation of transfer RNA molecules. The variant spectrum includes missense changes affecting critical catalytic residues, as well as nonsense and frameshift variants predicted to produce truncated, non-functional proteins. Most pathogenic variants follow an autosomal recessive inheritance pattern, meaning that individuals require changes in both gene copies to develop clinical features.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Pathogenic variants in PUS1 are primarily associated with mitochondrial myopathy, lactic acidosis, and sideroblastic anaemia (MLASA), also known as MLASA1. This condition typically presents in infancy or early childhood with muscle weakness, exercise intolerance, and severe anaemia characterised by iron-laden ring sideroblasts in bone marrow. Affected individuals often experience developmental delay and progressive neurological features. The severity and specific clinical presentation can vary among individuals, even within the same family, reflecting complex genotype-phenotype relationships and possible modifier effects.
No disease links recorded for this gene in our reference set.
UK clinical status
PUS1 appears on multiple NHS Genomic Medicine Service gene panels with green (high-evidence) classification. The gene is included in the Mitochondrial disorders panel and the Possible mitochondrial disorder - nuclear genes panel (R63), reflecting its established role in mitochondrial dysfunction. It also features on the Cytopenias and congenital anaemias panel and the Rare anaemia panel (R92), acknowledging the sideroblastic anaemia component of MLASA. Additional memberships include the Likely inborn error of metabolism panel (R98), Intellectual disability panel (R29), Undiagnosed metabolic disorders panel, and the Developmental Disorders Genotype-to-Phenotype database (DDG2P). This broad panel representation indicates that PUS1 testing may be considered across various clinical presentations involving mitochondrial energy metabolism, haematological abnormalities, or unexplained developmental concerns.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the PUS1 gene do?
PUS1 provides instructions for making an enzyme that modifies transfer RNA molecules by converting uridine to pseudouridine. This modification is essential for proper protein synthesis and mitochondrial function.
How are PUS1-related conditions inherited?
Conditions associated with PUS1 variants typically follow an autosomal recessive pattern, meaning an individual must inherit a pathogenic variant from both parents to develop clinical features. Carriers with one variant copy generally do not show symptoms.
What is MLASA syndrome?
MLASA (mitochondrial myopathy, lactic acidosis, and sideroblastic anaemia) is a rare inherited disorder caused by PUS1 variants. It presents with muscle weakness, elevated blood lactate, and severe anaemia with abnormal iron accumulation in developing red blood cells.