Multiple mitochondrial dysfunctions syndrome 10

Summary

Multiple mitochondrial dysfunctions syndrome 10 (MONDO:0975806) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple mitochondrial dysfunctions syndrome 10
Mondo ID	MONDO:0975806
OMIM	620960
UMLS	C5975413
MedGen	1874943
GARD	0027319
Is cancer (heuristic)	no

Data availability: 6 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › inherited lipoic acid biosynthesis defect › fatal multiple mitochondrial dysfunctions syndrome › multiple mitochondrial dysfunctions syndrome 10

Related subtypes (8): multiple mitochondrial dysfunctions syndrome 1, multiple mitochondrial dysfunctions syndrome 2, multiple mitochondrial dysfunctions syndrome 3, multiple mitochondrial dysfunctions syndrome 4, multiple mitochondrial dysfunctions syndrome 5, multiple mitochondrial dysfunctions syndrome 6, multiple mitochondrial dysfunctions syndrome 7, multiple mitochondrial dysfunctions syndrome 9b

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

6 retrieved; paginated sample, class counts are floors:

3 pathogenic, 1 benign/likely benign, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3341098	NM_004804.3(CIAO1):c.512A>G (p.Asp171Gly)	CIAO1	Pathogenic	no assertion criteria provided
3341099	NM_004804.3(CIAO1):c.752A>T (p.His251Leu)	CIAO1	Pathogenic	no assertion criteria provided
3341100	NM_004804.3:c.905A>C transversion, resulting in a his302-to-pro (H302P; 604333.0002)	CIAO1	Pathogenic	no assertion criteria provided
3341096	NM_004804.3(CIAO1):c.905A>C (p.His302Pro)	CIAO1	Likely pathogenic	criteria provided, single submitter
3341097	NM_004804.3(CIAO1):c.193C>T (p.Arg65Trp)	CIAO1	Uncertain significance	criteria provided, single submitter
241226	NM_017849.4(TMEM127):c.53C>T (p.Pro18Leu)	TMEM127	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 2 · 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
CIAO1	Limited	Autosomal recessive	multiple mitochondrial dysfunctions syndrome 10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM127	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
TMEM127	Orphanet:404511	Clear cell papillary renal cell carcinoma

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CIAO1	HGNC:14280	ENSG00000144021	O76071	Probable cytosolic iron-sulfur protein assembly protein CIAO1	gencc,clinvar
TMEM127	HGNC:26038	ENSG00000135956	O75204	Transmembrane protein 127	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIAO1	Probable cytosolic iron-sulfur protein assembly protein CIAO1	Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins.
TMEM127	Transmembrane protein 127	Controls cell proliferation acting as a negative regulator of TOR signaling pathway mediated by mTORC1.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIAO1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
TMEM127	Other/Unknown	no		TMEM127, TMEM127_TM

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left adrenal gland	1
left adrenal gland cortex	1
right adrenal gland cortex	1
blood	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIAO1	284	ubiquitous	marker	right adrenal gland cortex, left adrenal gland cortex, left adrenal gland
TMEM127	284	ubiquitous	marker	leukocyte, monocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CIAO1	2,747
TMEM127	709

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CIAO1	O76071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM127	O75204	77.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
Cytosolic iron-sulfur cluster assembly	1	761.3×	0.001	CIAO1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of TOR signaling	1	468.1×	0.009	TMEM127
iron-sulfur cluster assembly	1	300.9×	0.009	CIAO1
negative regulation of TOR signaling	1	280.9×	0.009	TMEM127
endosome organization	1	187.2×	0.011	TMEM127
chromosome segregation	1	86.9×	0.016	CIAO1
protein maturation	1	81.8×	0.016	CIAO1
negative regulation of cell population proliferation	1	21.1×	0.054	TMEM127
regulation of transcription by RNA polymerase II	1	5.8×	0.164	CIAO1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CIAO1	0	0
TMEM127	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	CIAO1, TMEM127

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CIAO1	0	—
TMEM127	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.