MT-ND4

Chr MT

NADH dehydrogenase subunit 4

Also known as: MTND4

NCBI Gene: 4538 ENSG00000198886 UniProt: P03905 OMIM: 516003

This gene encodes a subunit of NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial respiratory chain. Mutations cause MELAS, Leigh syndrome, and Leber hereditary optic neuropathy (LHON), with m.11778G>A being the most common LHON mutation. Inheritance is maternal through mitochondrial DNA, and disease severity depends on the degree of heteroplasmy in affected tissues.

GeneReviews OMIM ResearchSummary from Curated mito context

Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtLeber hereditary optic neuropathy

UniProtLeber hereditary optic neuropathy with dystonia

UniProtMitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome

Clinical highlights

Management implications

Idebenone is authorised in the EU for visual impairment in LHON.Applies when the variant causes LHON (m.11778G>A in MT-ND4, m.3460G>A in MT-ND1, m.14484T>C in MT-ND6 are the primary LHON variants); this gene's other diseases are not covered.

MT-ND4: treatable — idebenone

Gene–disease validity (ClinGen)

Active trials

Pubs (1 yr)

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P/LP submissions

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P/LP missense

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LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — MT-ND4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Treatment implicationsTreatable

Leber hereditary optic neuropathy (LHON)

Applies when the variant causes LHON (m.11778G>A in MT-ND4, m.3460G>A in MT-ND1, m.14484T>C in MT-ND6 are the primary LHON variants); this gene's other diseases are not covered.

Idebenone is authorised in the EU for visual impairment in LHON.

Treatment of choice

idebenone (Raxone) — EU-authorised 2015 for age 12 and over

EMA EPAR Raxone (authorised 8 Sep 2015). Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-10. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.

Nuclear-gene analyses omitted

MT-ND4 is a mitochondrial protein-coding gene. gnomAD constraint, carrier burden and exome coverage, the ClinVar type breakdown, AlphaFold and transcript-architecture views are built for nuclear genes and are not shown. Population data for mtDNA variants (gnomAD v3.1, homoplasmy and heteroplasmy) is on each variant page.

Where it sits in the mitochondrial genome

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proteinrRNAtRNAouter ring H-strand · inner L-strandMITOMAP confirmedreported (as of 2026-10-07)

37 genes from Ensembl (rCRS numbering, matched to MITOMAP’s Gene Loci); landmarks and disease alleles from MITOMAP (CC BY 3.0). Circular layout after MitoWheel.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

MT-ND4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

MITOMAP Disease Variants — MT-ND4

Live table ↗

Variant	AA	Disease	Status	GenBank seqs
m.11042T>C	Y95H	Biliary atresia	Reported	0
m.11048T>-	frameshift	Biliary atresia	Reported	0
m.11084A>G	T109A	AD, PD MELAS	Conflicting reports	230
m.11150G>A	A131T	Found in a Multiple Sclerosis patient	Reported	172
m.11232T>C	L158P	CPEO / Anaesthesia Hypersensitivity	Reported	0
m.11240C>T	L161F	Leigh Syndrome	Reported	0
m.11251A>G	L164L	Reduced risk of PD	Reported	6,227
m.11253T>C	I165T	LHON PD	Reported	366
m.11365T>C	A202A	found in HCM patient	Reported	143
m.11375A>C	K206Q	found in sCJD patient	Reported	0
m.11406T>A	L216H	MELAS	Reported	0
m.11467A>G	L236L	Altered brain pH / sCJD patients	Benign · reported	8,203
m.11470A>C	K237N	MELAS	Reported	0
m.11519A>C	T254P	ND4 mutation set found in a Multiple Sclerosis patient	Reported	0
m.11523A>C	K255T	ND4 mutation set found in a Multiple Sclerosis patient	Reported	0
m.11527C>T	H256H	ND4 mutation set found in a Multiple Sclerosis patient	Reported	31
m.11621TA>-	frameshift	CPEO, exercise intolerance	Uncertain significance · reported	0
m.11696G>A	V313I	LHON / LDYT / DEAF / hypertension helper mut.	Reported	374
m.11777C>A	R340S	Leigh Disease	Likely pathogenic · confirmed	0
m.11778G>A	R340H	LHON / Progressive Dystonia	Pathogenic · confirmed	191
m.11832G>A	W358Term	EXIT / oncocytoma	Reported	0
m.11874C>A	T372N	LHON	Reported	0
m.11914G>A	T385T	Possible susceptibility to bullous pemphigoid	Reported	7,230
m.11919C>T	S387F	Thyroid Cancer Cell Line	Reported	1
m.11984T>C	Y409H	Leigh Syndrome	Reported	67
m.11994C>T	T412I	Oligoasthenoteratozoospermia (OAT)	Conflicting reports	0
m.12015T>C	L419P	Atypical MELAS	Reported	3
m.12026A>G	I423V	DM	Reported	280
m.12027T>C	I423T	SZ-associated	Reported	2
m.12033A>G	N425S	LHON synergistic combo 10680A + 12033G + 14258A	Reported	24
m.12058A>C	E433D	Multisystemic disorder with SNHL and neurodevelopmental delay	Reported	0
m.12063C>T	T435I	Recurrent pregnancy loss	Reported	45