PUS1 – Myopathy, Lactic Acidosis, and Sideroblastic Anemia

Pseudouridylate synthase 1 (PUS1) encodes a dual-localized enzyme that catalyzes pseudouridylation of cytosolic and mitochondrial tRNAs, enhancing translation efficiency in both compartments. Pathogenic biallelic variants in PUS1 underlie myopathy, lactic acidosis, and sideroblastic anemia (MLASA), a rare autosomal recessive mitochondrial disorder. MLASA combines early-onset myopathy with exercise intolerance, lactic acidosis, and ringed sideroblasts in bone marrow.

Genetic studies in four unrelated families (10 probands) identified homozygous or compound heterozygous PUS1 variants associated with MLASA (PMID:15108122; PMID:17056637; PMID:32287105; PMID:39961824). Segregation of recessive PUS1 alleles was confirmed in six additional affected siblings (PMID:17056637; PMID:32287105; PMID:39961824). The variant spectrum includes missense (e.g., c.430C>G (p.Arg144Gly)), nonsense (c.658G>T (p.Glu220Ter)), and frameshift or splice-site changes resulting in loss of function.

Functional assays demonstrate that MLASA-associated PUS1 alleles abrogate pseudouridine synthase activity, leading to combined mitochondrial respiratory chain defects and reduced mtDNA-encoded protein synthesis in patient fibroblasts and muscle (PMID:15108122; PMID:17056637). Yeast Pus1 deletion models exhibit synthetic lethality with tRNA-decoding mutations and severe translation defects, underscoring the critical role of PUS1 in tRNA maturation (PMID:8641292; PMID:32392804).

The mechanism of pathogenicity is consistent with loss-of-function by deficient pseudouridylation of mitochondrial tRNAs and subsequent impaired oxidative phosphorylation in muscle and bone marrow. There is no conflicting evidence disputing this association.

Integration of genetic and experimental data supports a strong clinical validity for PUS1–MLASA. Additional variants continue to be described beyond the ClinGen genetic and functional caps.

Key Take-home: Biallelic PUS1 variants cause MLASA by loss of pseudouridine synthase activity leading to defective mitochondrial translation; genetic testing for PUS1 enables molecular diagnosis and informs management.

References

• American journal of human genetics • 2004 • Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA). PMID:15108122
• Journal of medical genetics • 2007 • Nonsense mutation in pseudouridylate synthase 1 (PUS1) in two brothers affected by myopathy, lactic acidosis and sideroblastic anaemia (MLASA). PMID:17056637
• Orphanet Journal of Rare Diseases • 2020 • MLASA plus phenotype in two Turkish sisters with a novel PUS1 p.Glu311Ter mutation. PMID:32287105
• Annals of hematology • 2025 • Identification of a novel truncated pathogenic variant in PUS1 gene in two siblings of consanguineous Tunisian family: intrafamilial phenotypic variability related to mtDNA copy number. PMID:39961824
• The EMBO journal • 1996 • Nuclear pore proteins are involved in the biogenesis of functional tRNA. PMID:8641292
• Biomolecules • 2020 • Impact of Pus1 Pseudouridine Synthase on Specific Decoding Events in Saccharomyces cerevisiae. PMID:32392804

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