Myopathy, lactic acidosis, and sideroblastic anemia 1

Summary

Myopathy, lactic acidosis, and sideroblastic anemia 1 (MONDO:0024553) is a disease caused by PUS1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PUS1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 104

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	myopathy, lactic acidosis, and sideroblastic anemia 1
Mondo ID	MONDO:0024553
OMIM	600462
DOID	DOID:0111185
UMLS	C4551958
MedGen	1634824
GARD	0025428
Is cancer (heuristic)	no

Also known as: mitochondrial myopathy and sideroblastic anaemia · MLASA1 · myopathy, lactic acidosis, and sideroblastic anaemia caused by mutation in PUS1 · myopathy, lactic acidosis, and sideroblastic anemia 1 · myopathy, lactic acidosis, and sideroblastic anemia caused by mutation in PUS1 · PUS1 myopathy, lactic acidosis, and sideroblastic anaemia · PUS1 myopathy, lactic acidosis, and sideroblastic anemia

Data availability: 104 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › myopathy, lactic acidosis, and sideroblastic anemia › myopathy, lactic acidosis, and sideroblastic anemia 1

Related subtypes (2): myopathy, lactic acidosis, and sideroblastic anemia 3, myopathy, lactic acidosis, and sideroblastic anemia 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

104 retrieved; paginated sample, class counts are floors:

30 uncertain significance, 19 likely pathogenic, 16 conflicting classifications of pathogenicity, 12 benign/likely benign, 10 likely benign, 9 pathogenic/likely pathogenic, 4 benign, 4 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2032014	NM_025215.6(PUS1):c.107_122del (p.Pro36fs)	LOC130009240	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678111	NM_025215.6(PUS1):c.107_122dup (p.Cys42fs)	LOC130009240	Pathogenic	criteria provided, single submitter
2029352	NM_025215.6(PUS1):c.418C>T (p.Gln140Ter)	LOC132090059	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442871	NM_025215.6(PUS1):c.45G>A (p.Trp15Ter)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452457	NM_025215.6(PUS1):c.482G>A (p.Trp161Ter)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804836	NM_025215.6(PUS1):c.70_74dup (p.Ser26fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2125434	NM_025215.6(PUS1):c.916A>T (p.Lys306Ter)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137450	NM_025215.6(PUS1):c.460C>T (p.Gln154Ter)	PUS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2536	NM_025215.6(PUS1):c.430C>T (p.Arg144Trp)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2537	NM_025215.6(PUS1):c.658G>T (p.Glu220Ter)	PUS1	Pathogenic	no assertion criteria provided
423712	NM_025215.6(PUS1):c.454dup (p.Ala152fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
587566	NM_025215.6(PUS1):c.813del (p.Phe272fs)	PUS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
691962	NM_025215.6(PUS1):c.1122C>G (p.Tyr374Ter)	PUS1	Pathogenic	no assertion criteria provided
2678112	NM_025215.6(PUS1):c.130dup (p.Gln44fs)	LOC130009240	Likely pathogenic	criteria provided, single submitter
4081774	NM_025215.6(PUS1):c.441+1G>A	LOC132090059	Likely pathogenic	criteria provided, single submitter
221982	NM_025215.6(PUS1):c.883C>T (p.Arg295Trp)	PUS1	Likely pathogenic	criteria provided, single submitter
2678106	NM_025215.6(PUS1):c.442-1G>T	PUS1	Likely pathogenic	criteria provided, single submitter
2678107	NM_025215.6(PUS1):c.545-1G>A	PUS1	Likely pathogenic	criteria provided, single submitter
2678108	NM_025215.6(PUS1):c.877C>T (p.Gln293Ter)	PUS1	Likely pathogenic	criteria provided, single submitter
2678109	NM_025215.6(PUS1):c.1237-2A>G	PUS1	Likely pathogenic	criteria provided, single submitter
2678110	NM_025215.6(PUS1):c.178del (p.Glu60fs)	PUS1	Likely pathogenic	criteria provided, single submitter
2678113	NM_025215.6(PUS1):c.517del (p.His173fs)	PUS1	Likely pathogenic	criteria provided, single submitter
2678114	NM_025215.6(PUS1):c.929del (p.Pro310fs)	PUS1	Likely pathogenic	criteria provided, single submitter
2678115	NM_025215.6(PUS1):c.893_896del (p.Val298fs)	PUS1	Likely pathogenic	criteria provided, single submitter
3031648	NM_025215.6(PUS1):c.1156dup (p.Ser386fs)	PUS1	Likely pathogenic	criteria provided, single submitter
3032548	NM_025215.6(PUS1):c.2T>G (p.Met1Arg)	PUS1	Likely pathogenic	criteria provided, single submitter
3065505	NM_025215.6(PUS1):c.462_463dup (p.Val155fs)	PUS1	Likely pathogenic	criteria provided, single submitter
3574397	NM_025215.6(PUS1):c.1A>T (p.Met1Leu)	PUS1	Likely pathogenic	criteria provided, single submitter
3574398	NM_025215.6(PUS1):c.276T>A (p.Tyr92Ter)	PUS1	Likely pathogenic	criteria provided, single submitter
3574399	NM_025215.6(PUS1):c.731_734dup (p.Phe245fs)	PUS1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PUS1	Definitive	Autosomal recessive	myopathy, lactic acidosis, and sideroblastic anemia 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PUS1	Orphanet:2598	Mitochondrial myopathy and sideroblastic anemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PUS1	HGNC:15508	ENSG00000177192	Q9Y606	Pseudouridylate synthase 1 homolog	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PUS1	Pseudouridylate synthase 1 homolog	Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PUS1	Enzyme (other)	yes	5.4.99.B22	PsdUridine_synth_TruA, TruA/RsuA/RluB/E/F_N, PsdUridine_synth_TruA_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
lower esophagus mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PUS1	229	ubiquitous	marker	granulocyte, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PUS1	2,688

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PUS1	Q9Y606	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the mitochondrion	1	1038.2×	0.002	PUS1
tRNA modification in the nucleus and cytosol	1	292.8×	0.003	PUS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial tRNA pseudouridine synthesis	1	5617.3×	0.001	PUS1
tRNA pseudouridine synthesis	1	2808.7×	0.001	PUS1
mRNA pseudouridine synthesis	1	1685.2×	0.001	PUS1
RNA splicing	1	88.2×	0.015	PUS1
mRNA processing	1	78.8×	0.015	PUS1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	PUS1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PUS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PUS1	6	Binding:6

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PUS1	5.4.99.B22

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PUS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PUS1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.