mitochondrial complex I deficiency, nuclear type 29

Summary

mitochondrial complex I deficiency, nuclear type 29 (MONDO:0032633) is a disease caused by TMEM126B (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: TMEM126B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial complex I deficiency, nuclear type 29
Mondo ID	MONDO:0032633
OMIM	618250
DOID	DOID:0112084
UMLS	C4748830
MedGen	1648451
GARD	0016330
Is cancer (heuristic)	no

Also known as: MC1DN29

Data availability: 11 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › mitochondrial respiratory chain complex deficiency › mitochondrial complex I deficiency › mitochondrial complex I deficiency, nuclear type › mitochondrial complex I deficiency, nuclear type 29

Related subtypes (36): mitochondrial complex I deficiency, nuclear type 12, mitochondrial complex I deficiency, nuclear type 30, Leber hereditary optic neuropathy, autosomal recessive, mitochondrial complex I deficiency, nuclear type 36, mitochondrial complex I deficiency, nuclear type 37, mitochondrial complex I deficiency, nuclear type 2, mitochondrial complex I deficiency, nuclear type 3, mitochondrial complex I deficiency, nuclear type 4, mitochondrial complex I deficiency, nuclear type 5, mitochondrial complex I deficiency, nuclear type 6, mitochondrial complex I deficiency, nuclear type 7, mitochondrial complex I deficiency, nuclear type 8, mitochondrial complex I deficiency, nuclear type 9, mitochondrial complex I deficiency, nuclear type 10, mitochondrial complex I deficiency, nuclear type 11, mitochondrial complex I deficiency, nuclear type 13, mitochondrial complex I deficiency, nuclear type 14, mitochondrial complex I deficiency, nuclear type 15, mitochondrial complex I deficiency, nuclear type 16, mitochondrial complex I deficiency, nuclear type 17, mitochondrial complex I deficiency, nuclear type 18, mitochondrial complex I deficiency, nuclear type 19, mitochondrial complex I deficiency, nuclear type 21, mitochondrial complex I deficiency, nuclear type 22, mitochondrial complex I deficiency, nuclear type 23, mitochondrial complex I deficiency, nuclear type 24, mitochondrial complex I deficiency, nuclear type 25, mitochondrial complex I deficiency, nuclear type 26, mitochondrial complex I deficiency, nuclear type 27, mitochondrial complex I deficiency, nuclear type 28, mitochondrial complex I deficiency, nuclear type 31, mitochondrial complex I deficiency, nuclear type 32, mitochondrial complex I deficiency, nuclear type 33, mitochondrial complex I deficiency, nuclear type 34, mitochondrial complex I deficiency, nuclear type 1, mitochondrial complex I deficiency, nuclear type 39

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

11 retrieved; paginated sample, class counts are floors:

5 pathogenic/likely pathogenic, 3 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032805	NM_018480.7(TMEM126B):c.320_321del (p.Tyr107fs)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339485	NM_018480.7(TMEM126B):c.421_422del (p.Val141fs)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1431700	NM_018480.7(TMEM126B):c.241del (p.Thr81fs)	TMEM126B	Pathogenic	criteria provided, multiple submitters, no conflicts
236208	NM_018480.7(TMEM126B):c.401del (p.Asn134fs)	TMEM126B	Pathogenic	no assertion criteria provided
236209	NM_018480.7(TMEM126B):c.635G>T (p.Gly212Val)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253166	NM_018480.7(TMEM126B):c.397G>A (p.Asp133Asn)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
253167	NM_018480.7(TMEM126B):c.208C>T (p.Gln70Ter)	TMEM126B	Pathogenic	no assertion criteria provided
997635	NM_018480.7(TMEM126B):c.137del (p.Ala46fs)	TMEM126B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2630644	NM_018480.7(TMEM126B):c.290dup (p.Lys98fs)	TMEM126B	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2077431	NM_018480.7(TMEM126B):c.626T>C (p.Ile209Thr)	TMEM126B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4277627	NM_001372123.1(IKZF5):c.202G>A (p.Gly68Arg)	IKZF5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
TMEM126B	Definitive	Autosomal recessive	mitochondrial complex I deficiency, nuclear type 29	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TMEM126B	Orphanet:2609	Isolated complex I deficiency
IKZF5	Orphanet:168629	Autosomal thrombocytopenia with normal platelets

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
TMEM126B	HGNC:30883	ENSG00000171204	Q8IUX1	Complex I assembly factor TMEM126B, mitochondrial	gencc,clinvar
IKZF5	HGNC:14283	ENSG00000095574	Q9H5V7	Zinc finger protein Pegasus	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TMEM126B	Complex I assembly factor TMEM126B, mitochondrial	As part of the MCIA complex, involved in the assembly of the mitochondrial complex I.
IKZF5	Zinc finger protein Pegasus	Transcriptional repressor that binds the core 5’GNNTGTNG-3’ DNA consensus sequence.

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TMEM126B	Other/Unknown	no		TMEM126
IKZF5	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Ikaros_C2H2-ZF

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
C1 segment of cervical spinal cord	2
islet of Langerhans	1
pigmented layer of retina	1
body of pancreas	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TMEM126B	283	ubiquitous	marker	pigmented layer of retina, C1 segment of cervical spinal cord, islet of Langerhans
IKZF5	262	ubiquitous	marker	endothelial cell, body of pancreas, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TMEM126B	1,325
IKZF5	965

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TMEM126B	Q8IUX1	82.06
IKZF5	Q9H5V7	54.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Complex I biogenesis	1	165.5×	0.015	TMEM126B
Respiratory electron transport	1	95.2×	0.015	TMEM126B
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	TMEM126B
Metabolism	1	11.6×	0.086	TMEM126B

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
response to food	1	247.8×	0.010	TMEM126B
mitochondrial respiratory chain complex I assembly	1	205.5×	0.010	TMEM126B
negative regulation of transcription by RNA polymerase II	1	8.9×	0.146	IKZF5
regulation of transcription by RNA polymerase II	1	5.8×	0.164	IKZF5

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
TMEM126B	0	0
IKZF5	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	TMEM126B, IKZF5

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)
TMEM126B	0	—
IKZF5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.