Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

Summary

Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome (MONDO:0044714) is a disease caused by MSTO1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MSTO1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 43
• Phenotypes (HPO): 47

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000347	Micrognathia	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000601	Hypotelorism	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0000786	Primary amenorrhea	Frequent (30-79%)
HP:0000836	Hyperthyroidism	Frequent (30-79%)
HP:0000870	Increased circulating prolactin concentration	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Frequent (30-79%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001310	Dysmetria	Frequent (30-79%)
HP:0001321	Cerebellar hypoplasia	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0002073	Progressive cerebellar ataxia	Frequent (30-79%)
HP:0002075	Dysdiadochokinesis	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002761	Generalized joint laxity	Frequent (30-79%)
HP:0003326	Myalgia	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0003737	Mitochondrial myopathy	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008180	Mildly elevated creatine kinase	Frequent (30-79%)
HP:0009051	Increased muscle glycogen content	Frequent (30-79%)
HP:0012032	Lipoma	Frequent (30-79%)
HP:0012240	Increased intramyocellular lipid droplets	Frequent (30-79%)
HP:0030319	Weakness of facial musculature	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0100874	Thick hair	Frequent (30-79%)
HP:0100887	Abnormality of globe size	Frequent (30-79%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0100753	Schizophrenia	Occasional (5-29%)
HP:0000543	Optic disc pallor	Very rare (<1-4%)
HP:0000580	Pigmentary retinopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome
Mondo ID	MONDO:0044714
OMIM	617675
Orphanet	502423
UMLS	C4540096
MedGen	1620960
GARD	0017934
Is cancer (heuristic)	no

Also known as: mitochondrial myopathy-cerebellar atrophy-pigmentary retinopathy syndrome · MMYAT

Data availability: 43 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, mitochondrial encephalomyopathy, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

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

43 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 8 conflicting classifications of pathogenicity, 7 pathogenic, 3 likely pathogenic, 3 pathogenic/likely pathogenic, 1 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3571457	GRCh38/hg38 1q22(chr1:155610587-155746587)x1	DAP3	Pathogenic	criteria provided, single submitter
3336212	NM_018116.4(MSTO1):c.1190G>A (p.Trp397Ter)	MSTO1	Pathogenic	criteria provided, single submitter
4293810	NM_018116.4(MSTO1):c.595del (p.Glu199fs)	MSTO1	Pathogenic	criteria provided, single submitter
438832	NM_018116.4(MSTO1):c.1128C>A (p.Phe376Leu)	MSTO1	Pathogenic	no assertion criteria provided
504109	NM_018116.4(MSTO1):c.1259del (p.Gly420fs)	MSTO1	Pathogenic	criteria provided, multiple submitters, no conflicts
590277	NM_018116.4(MSTO1):c.836G>A (p.Arg279His)	MSTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
977147	NM_018116.4(MSTO1):c.706G>C (p.Asp236His)	MSTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
985820	NM_018116.4(MSTO1):c.887_888del (p.Leu296fs)	MSTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
987949	NM_018116.4(MSTO1):c.1099-1G>A	MSTO1	Pathogenic	criteria provided, multiple submitters, no conflicts
987950	NM_018116.4(MSTO1):c.79C>T (p.Gln27Ter)	MSTO1	Pathogenic	no assertion criteria provided
438831	NM_018116.4(MSTO1):c.1033C>T (p.Arg345Cys)	MSTO1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
438834	NM_018116.4(MSTO1):c.966+1G>A	MSTO1	Likely pathogenic	criteria provided, single submitter
522862	NM_018116.4(MSTO1):c.676C>T (p.Gln226Ter)	MSTO1	Likely pathogenic	criteria provided, single submitter
1033468	NM_018116.4(MSTO1):c.1229G>A (p.Arg410His)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691765	NM_018116.4(MSTO1):c.1435C>T (p.Pro479Ser)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1693164	NM_018116.4(MSTO1):c.220+5G>C	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1710255	NM_018116.4(MSTO1):c.716C>A (p.Ser239Tyr)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3388048	NM_018116.4(MSTO1):c.268C>T (p.Gln90Ter)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438833	NM_018116.4(MSTO1):c.971C>T (p.Thr324Ile)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
438835	NM_018116.4(MSTO1):c.22G>A (p.Val8Met)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
684407	NM_018116.4(MSTO1):c.651C>G (p.Phe217Leu)	MSTO1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033466	NM_018116.4(MSTO1):c.1024G>A (p.Val342Ile)	MSTO1	Uncertain significance	criteria provided, single submitter
1033467	NM_018116.4(MSTO1):c.1059G>A (p.Met353Ile)	MSTO1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1676832	NM_018116.4(MSTO1):c.422-3C>G	MSTO1	Uncertain significance	criteria provided, single submitter
1684294	NM_018116.4(MSTO1):c.1600C>T (p.Arg534Cys)	MSTO1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1810197	NM_018116.4(MSTO1):c.725G>A (p.Gly242Asp)	MSTO1	Uncertain significance	criteria provided, single submitter
2433808	NM_018116.4(MSTO1):c.1034G>A (p.Arg345His)	MSTO1	Uncertain significance	criteria provided, single submitter
2441561	NM_018116.4(MSTO1):c.767G>A (p.Arg256Gln)	MSTO1	Uncertain significance	criteria provided, single submitter
2572507	NM_018116.4(MSTO1):c.262G>T (p.Asp88Tyr)	MSTO1	Uncertain significance	criteria provided, single submitter
3065171	NM_018116.4(MSTO1):c.280G>A (p.Ala94Thr)	MSTO1	Uncertain significance	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
MSTO1	Definitive	Autosomal recessive	mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MSTO1	Orphanet:502423	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MSTO1	HGNC:29678	ENSG00000125459	Q9BUK6	Protein misato homolog 1	gencc,clinvar
DAP3	HGNC:2673	ENSG00000132676	P51398	Small ribosomal subunit protein mS29	clinvar
DLGAP3	HGNC:30368	ENSG00000116544	O95886	Disks large-associated protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MSTO1	Protein misato homolog 1	Involved in the regulation of mitochondrial distribution and morphology.
DAP3	Small ribosomal subunit protein mS29	As a component of the mitochondrial small ribosomal subunit, it plays a role in the translation of mitochondrial mRNAs.
DLGAP3	Disks large-associated protein 3	May play a role in the molecular organization of synapses and neuronal cell signaling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MSTO1	Other/Unknown	no		Misato_II_tubulin-like, DML1/Misato_tubulin, Tubulin/FtsZ_GTPase_sf
DAP3	Other/Unknown	no		Ribosomal_mS29_met, Ribosomal_mS29, P-loop_NTPase
DLGAP3	Other/Unknown	no		SAPAP

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
right testis	1
testis	1
adrenal tissue	1
body of pancreas	1
colonic epithelium	1
anterior cingulate cortex	1
nucleus accumbens	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MSTO1	134	tissue_specific	marker	left testis, right testis, testis
DAP3	294	ubiquitous	marker	body of pancreas, adrenal tissue, colonic epithelium
DLGAP3	150	broad	yes	right frontal lobe, anterior cingulate cortex, nucleus accumbens

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DAP3	3,504
DLGAP3	1,613
MSTO1	1,025

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DAP3	P51398	77

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MSTO1	Q9BUK6	83.83
DLGAP3	O95886	50.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neurexins and neuroligins	1	98.5×	0.024	DLGAP3
Mitochondrial translation	1	68.8×	0.024	DAP3
Mitochondrial translation initiation	1	63.4×	0.024	DAP3
Mitochondrial translation elongation	1	63.4×	0.024	DAP3
Mitochondrial ribosome-associated quality control	1	61.4×	0.024	DAP3
Mitochondrial translation termination	1	54.9×	0.024	DAP3
Translation	1	31.0×	0.037	DAP3
Metabolism of proteins	1	6.2×	0.155	DAP3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of mitochondrial fusion	1	1123.5×	0.004	MSTO1
mitochondrion distribution	1	702.2×	0.004	MSTO1
modification of postsynaptic structure	1	624.1×	0.004	DLGAP3
signaling	1	510.7×	0.004	DLGAP3
apoptotic mitochondrial changes	1	295.6×	0.006	DAP3
apoptotic signaling pathway	1	74.9×	0.019	DAP3
modulation of chemical synaptic transmission	1	61.1×	0.019	DLGAP3
mitochondrial translation	1	57.9×	0.019	DAP3
mitochondrion organization	1	50.6×	0.020	MSTO1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MSTO1	0	0
DAP3	0	0
DLGAP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
DAP3	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	MSTO1, DAP3, DLGAP3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MSTO1	0	—
DAP3	2	—
DLGAP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.