acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Summary

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins (MONDO:0013111) is a disease caused by TRMU (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: TRMU (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 258

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		32	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
Mondo ID	MONDO:0013111
OMIM	613070
Orphanet	217371
DOID	DOID:0080778
UMLS	C3278664
MedGen	480294
GARD	0010593
Is cancer (heuristic)	no

Also known as: acute infantile liver failure · acute infantile liver failure due to synthesis defect of mitochondrial DNA-encoded proteins · acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins · infantile liver failure caused by mutation in TRMU · LFIT · liver failure, infantile, transient · liver failure, transient infantile · transient infantile liver failure · TRMU infantile liver failure

Data availability: 258 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › infantile liver failure › acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Related subtypes (3): infantile liver failure syndrome 2, infantile liver failure syndrome 1, infantile liver failure syndrome 3

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

258 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 66 likely pathogenic, 35 conflicting classifications of pathogenicity, 33 pathogenic/likely pathogenic, 22 pathogenic, 13 benign, 12 likely benign, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3075734	NM_018006.5:c.[2T>A];[835G>A]		Pathogenic	criteria provided, single submitter
214577	NM_020117.11(LARS1):c.3313C>T (p.Arg1105Ter)	LARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4688932	NM_020117.11(LARS1):c.1812del (p.Phe603_Tyr604insTer)	LARS1	Pathogenic	criteria provided, single submitter
1696343	NM_015909.4(NBAS):c.1A>T (p.Met1Leu)	LOC129933155	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076261	NM_015909.4(NBAS):c.2827G>T (p.Glu943Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1335898	NM_015909.4(NBAS):c.1213C>T (p.Arg405Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1403703	NM_015909.4(NBAS):c.4370_4371delinsGA (p.Tyr1457Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1406108	NM_015909.4(NBAS):c.1628_1629insA (p.Ser544fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
1804805	NM_015909.4(NBAS):c.4520del (p.Leu1507fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2011558	NM_015909.4(NBAS):c.4838_4839del (p.Val1613fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2159340	NM_015909.4(NBAS):c.500_501del (p.Phe167fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
218416	NM_015909.4(NBAS):c.409C>T (p.Arg137Trp)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2446020	NM_015909.4(NBAS):c.5547del (p.Trp1850fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
2682590	NM_015909.4(NBAS):c.5356C>T (p.Arg1786Ter)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
2996842	NM_015909.4(NBAS):c.3683_3689dup (p.Leu1231fs)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
3385250	NM_015909.4(NBAS):c.1284G>A (p.Trp428Ter)	NBAS	Pathogenic	criteria provided, single submitter
37042	NM_015909.4(NBAS):c.5741G>A (p.Arg1914His)	NBAS	Pathogenic	criteria provided, multiple submitters, no conflicts
4526189	NC_000002.11:g.(?15307039)(15378811_15415607)del	NBAS	Pathogenic	criteria provided, single submitter
4689595	NC_000002.11:g.(15307448_15319111)_(15679481_15691616)del	NBAS	Pathogenic	criteria provided, single submitter
501319	NM_015909.4(NBAS):c.2950del (p.Ile984fs)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617879	NM_015909.4(NBAS):c.6840G>A (p.Thr2280=)	NBAS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071658	NM_018006.5(TRMU):c.803del (p.Ala268fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076201	NM_018006.5(TRMU):c.880_898del (p.Arg294fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076499	NM_018006.5(TRMU):c.706-1G>A	TRMU	Pathogenic	criteria provided, multiple submitters, no conflicts
1291	NM_018006.5(TRMU):c.229T>C (p.Tyr77His)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1293	NM_018006.5(TRMU):c.815G>A (p.Gly272Asp)	TRMU	Pathogenic	no assertion criteria provided
1294	NM_018006.5(TRMU):c.2T>A (p.Met1Lys)	TRMU	Pathogenic	no assertion criteria provided
1355265	NM_018006.5(TRMU):c.87C>G (p.Tyr29Ter)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1444343	NM_018006.5(TRMU):c.172_173dup (p.Arg59fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1908686	NM_018006.5(TRMU):c.880dup (p.Arg294fs)	TRMU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 8 · 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
TRMU	Definitive	Autosomal recessive	acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRMU	Orphanet:217371	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins
TRMU	Orphanet:254864	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency
TRMU	Orphanet:90641	Rare mitochondrial non-syndromic sensorineural deafness
NBAS	Orphanet:391677	Short stature-optic atrophy-Pelger-Huët anomaly syndrome
NBAS	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
LARS1	Orphanet:370088	Acute infantile liver failure-multisystemic involvement syndrome
MMUT	Orphanet:289916	Vitamin B12-unresponsive methylmalonic acidemia type mut0
MMUT	Orphanet:79312	Vitamin B12-unresponsive methylmalonic acidemia type mut-

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TRMU	HGNC:25481	ENSG00000100416	O75648	Mitochondrial tRNA-specific 2-thiouridylase 1	gencc,clinvar
NBAS	HGNC:15625	ENSG00000151779	A2RRP1	NBAS subunit of NRZ tethering complex	clinvar
LARS1	HGNC:6512	ENSG00000133706	Q9P2J5	Leucine–tRNA ligase, cytoplasmic	clinvar
MMUT	HGNC:7526	ENSG00000146085	P22033	Methylmalonyl-CoA mutase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TRMU	Mitochondrial tRNA-specific 2-thiouridylase 1	Catalyzes the 2-thiolation of uridine at the wobble position (U34) of mitochondrial tRNA(Lys), tRNA(Glu) and tRNA(Gln).
NBAS	NBAS subunit of NRZ tethering complex	Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
LARS1	Leucine–tRNA ligase, cytoplasmic	Aminoacyl-tRNA synthetase that catalyzes the specific attachment of leucine to its cognate tRNA (tRNA(Leu)).
MMUT	Methylmalonyl-CoA mutase, mitochondrial	Catalyzes the reversible isomerization of methylmalonyl-CoA (MMCoA) (generated from branched-chain amino acid metabolism and degradation of dietary odd chain fatty acids and cholesterol) to succinyl-CoA (3-carboxypropionyl-CoA), a key inte…

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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)	3	9.0×	0.004
Scaffold/PPI	1	4.3×	0.212

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TRMU	Enzyme (other)	yes	2.1.1.61	MnmA-like, Rossmann-like_a/b/a_fold, MnmA-like_central_sf
NBAS	Scaffold/PPI	no		Quino_amine_DH_bsu, Sec39_domain, WD40/YVTN_repeat-like_dom_sf
LARS1	Enzyme (other)	yes	6.1.1.4	aa-tRNA-synth_I_CS, aa-tRNA-synth_Ia, Leu-tRNA-synth_Ia_arc/euk
MMUT	Enzyme (other)	yes	5.4.99.2	MMCoA_mutase_a_cat, MeMalonylCoA_mutase_a/b_cat, Cobalamin-bd

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
apex of heart	1
metanephros cortex	1
right hemisphere of cerebellum	1
calcaneal tendon	1
primordial germ cell in gonad	1
Brodmann (1909) area 23	1
endothelial cell	1
choroid plexus epithelium	1
nephron tubule	1
oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TRMU	259	ubiquitous	marker	apex of heart, right hemisphere of cerebellum, metanephros cortex
NBAS	293	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, ventricular zone
LARS1	292	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, ventricular zone
MMUT	296	ubiquitous	marker	choroid plexus epithelium, oocyte, nephron tubule

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MMUT	3,709
LARS1	3,514
TRMU	1,739
NBAS	1,134

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
LARS1	Q9P2J5	7
MMUT	P22033	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TRMU	O75648	89.60
NBAS	A2RRP1	74.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective MMAA causes MMA, cblA type	1	1427.5×	0.006	MMUT
Defective MUT causes MMAM	1	1427.5×	0.006	MMUT
Diseases of mitochondrial beta oxidation	1	1427.5×	0.006	MMUT
Diseases of propionyl-CoA catabolism	1	1427.5×	0.006	MMUT
Propionyl-CoA catabolism	1	571.0×	0.012	MMUT
Cobalamin (Cbl) metabolism	1	317.2×	0.018	MMUT
tRNA modification in the mitochondrion	1	259.6×	0.019	TRMU
Defects in cobalamin (B12) metabolism	1	203.9×	0.021	MMUT
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	158.6×	0.023	MMUT
Defects in vitamin and cofactor metabolism	1	150.3×	0.023	MMUT
Cytosolic tRNA aminoacylation	1	109.8×	0.028	LARS1
Mitochondrial Fatty Acid Beta-Oxidation	1	95.2×	0.029	MMUT
tRNA processing	1	89.2×	0.029	TRMU
tRNA Aminoacylation	1	71.4×	0.034	LARS1
Selenoamino acid metabolism	1	49.2×	0.044	LARS1
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.044	MMUT
Transcriptional and post-translational regulation of MITF-M expression and activity	1	44.6×	0.044	LARS1
Golgi-to-ER retrograde transport	1	33.2×	0.054	NBAS
Fatty acid metabolism	1	32.8×	0.054	MMUT
Metabolism of vitamins and cofactors	1	29.1×	0.055	MMUT
MITF-M-regulated melanocyte development	1	28.6×	0.055	LARS1
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.055	NBAS
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.056	NBAS
Metabolism	2	5.8×	0.056	LARS1, MMUT
Diseases of metabolism	1	20.1×	0.066	MMUT
Metabolism of amino acids and derivatives	1	16.9×	0.076	LARS1
Translation	1	15.5×	0.079	LARS1
Metabolism of RNA	1	10.4×	0.112	TRMU
Membrane Trafficking	1	9.3×	0.121	NBAS
Vesicle-mediated transport	1	8.7×	0.125	NBAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete propionate metabolic process, methylmalonyl pathway	1	4213.0×	0.002	MMUT
glutaminyl-tRNA aminoacylation	1	2106.5×	0.002	LARS1
leucyl-tRNA aminoacylation	1	2106.5×	0.002	LARS1
succinyl-CoA biosynthetic process	1	2106.5×	0.002	MMUT
tRNA wobble position uridine thiolation	1	1053.2×	0.003	TRMU
homocysteine metabolic process	1	468.1×	0.005	MMUT
negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	468.1×	0.005	NBAS
cellular response to L-leucine	1	351.1×	0.006	LARS1
cellular response to leucine starvation	1	351.1×	0.006	LARS1
tRNA aminoacylation for protein translation	1	210.7×	0.009	LARS1
nuclear-transcribed mRNA catabolic process	1	191.5×	0.009	NBAS
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	84.3×	0.016	NBAS
cellular response to amino acid starvation	1	79.5×	0.016	LARS1
cellular response to amino acid stimulus	1	76.6×	0.016	LARS1
positive regulation of TORC1 signaling	1	73.9×	0.016	LARS1
positive regulation of GTPase activity	1	69.1×	0.016	MMUT
post-embryonic development	1	51.4×	0.020	MMUT
protein transport	1	11.0×	0.088	NBAS

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TRMU	0	0
NBAS	0	0
LARS1	0	0
MMUT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
LARS1	35	Binding:32, ADMET:2, Functional:1
NBAS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TRMU	2.1.1.61	tRNA 5-(aminomethyl)-2-thiouridylate-methyltransferase
LARS1	6.1.1.4	leucine-tRNA ligase
MMUT	5.4.99.2	methylmalonyl-CoA mutase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	2	LARS1, MMUT
D	Druggable family + AlphaFold only, no drug	1	TRMU
E	Difficult family or no structure, no drug	1	NBAS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TRMU	0	—
NBAS	1	—
LARS1	35	—
MMUT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.