Lipoyl transferase 1 deficiency

Summary

Lipoyl transferase 1 deficiency (MONDO:0014576) is a disease caused by variants in LIPT1 and LIPT2, with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: LIPT1 (GenCC Strong), LIPT2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 17

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	lipoyl transferase 1 deficiency
Mondo ID	MONDO:0014576
OMIM	616299
Orphanet	401862
UMLS	C4225379
MedGen	904073
GARD	0012680
Is cancer (heuristic)	no

Also known as: lipoyltransferase 1 deficiency · LIPT1D

Data availability: 17 ClinVar variants · 7 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 › inherited lipoic acid biosynthesis defect › lipoyl transferase 1 deficiency

Related subtypes (5): pyruvate dehydrogenase E3 deficiency, lipoic acid synthetase deficiency, spasticity-ataxia-gait anomalies syndrome, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, fatal multiple mitochondrial dysfunctions syndrome

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

17 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 4 likely pathogenic, 3 pathogenic, 3 conflicting classifications of pathogenicity, 2 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
424785	NM_145199.2(LIPT1):c.[806G>A];[980T>G]		Pathogenic	criteria provided, single submitter
433560	NM_015929.3(LIPT1):c.[131A>G];[875C>G]		Pathogenic	no assertion criteria provided
189834	NM_145199.3(LIPT1):c.535A>G (p.Thr179Ala)	LIPT1	Pathogenic	no assertion criteria provided
285871	NM_145199.3(LIPT1):c.875C>G (p.Ser292Ter)	LIPT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189835	NM_145199.3(LIPT1):c.212C>T (p.Ser71Phe)	LIPT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
242526	NM_145199.3(LIPT1):c.806G>A (p.Trp269Ter)	LIPT1	Likely pathogenic	criteria provided, single submitter
3377019	NM_145199.3(LIPT1):c.244C>T (p.Gln82Ter)	LIPT1	Likely pathogenic	criteria provided, single submitter
433559	NM_145199.3(LIPT1):c.131A>G (p.Asn44Ser)	LIPT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
189836	NM_145199.3(LIPT1):c.292C>G (p.Arg98Gly)	LIPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3063680	NM_145199.3(LIPT1):c.368del (p.Lys123fs)	LIPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420362	NM_145199.3(LIPT1):c.369del (p.Lys123fs)	LIPT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1399147	NM_145199.3(LIPT1):c.587C>T (p.Pro196Leu)	LIPT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1802992	NM_145199.3(LIPT1):c.316G>A (p.Val106Ile)	LIPT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2429373	NM_145199.3(LIPT1):c.578T>C (p.Leu193Pro)	LIPT1	Uncertain significance	criteria provided, single submitter
973443	NM_145199.3(LIPT1):c.539T>C (p.Leu180Ser)	LIPT1	Uncertain significance	criteria provided, single submitter
379992	NM_145199.3(LIPT1):c.711T>C (p.Ala237=)	LIPT1	Benign	criteria provided, multiple submitters, no conflicts
379991	NM_145199.3(LIPT1):c.565T>C (p.Leu189=)	MITD1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
LIPT1	Strong	Autosomal recessive	lipoyl transferase 1 deficiency	7
LIPT2	Strong	Autosomal recessive	lipoyl transferase 1 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LIPT1	Orphanet:401862	Lipoyl transferase 1 deficiency

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
LIPT1	HGNC:29569	ENSG00000144182	Q9Y234	Lipoyl amidotransferase LIPT1, mitochondrial	gencc,clinvar
LIPT2	HGNC:37216	ENSG00000175536	A6NK58	Octanoyl-[acyl-carrier-protein]:protein N-octanoyltransferase LIPT2, mitochondrial	gencc
MITD1	HGNC:25207	ENSG00000158411	Q8WV92	MIT domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LIPT1	Lipoyl amidotransferase LIPT1, mitochondrial	Lipoyl amidotransferase that catalyzes the transfer of lipoyl moieties from lipoyl-protein H of the glycine cleavage system (lipoyl-GCSH) to E2 subunits of the pyruvate dehydrogenase complex (PDCE2).
LIPT2	Octanoyl-[acyl-carrier-protein]:protein N-octanoyltransferase LIPT2, mitochondrial	Catalyzes the transfer of endogenously produced octanoic acid from octanoyl-acyl-carrier-protein (octanoyl-ACP) onto the lipoyl domains of lipoate-dependent enzymes such as the protein H of the glycine cleavage system (GCSH).
MITD1	MIT domain-containing protein 1	Required for efficient abscission at the end of cytokinesis, together with components of the ESCRT-III complex.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LIPT1	Other/Unknown	no		BPL_LPL_catalytic, LipoylTrfase_LipoateP_Ligase, aa-tRNA-synth_II/BPL/LPL
LIPT2	Enzyme (other)	yes	2.3.1.181	Octanoyltransferase, BPL_LPL_catalytic, aa-tRNA-synth_II/BPL/LPL
MITD1	Other/Unknown	no		MIT_dom, MITD1_C, MIT_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
calcaneal tendon	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
left testis	1
monocyte	1
vermiform appendix	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LIPT1	287	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon
LIPT2	134	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, left testis
MITD1	250	ubiquitous	marker	calcaneal tendon, monocyte, vermiform appendix

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MITD1	1,187
LIPT1	1,165
LIPT2	617

Intra-cohort edges

A	B	Sources
LIPT1	LIPT2	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MITD1	Q8WV92	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LIPT2	A6NK58	93.37
LIPT1	Q9Y234	91.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Protein lipoylation	2	1038.2×	3e-06	LIPT1, LIPT2
Post-translational protein modification	2	19.2×	0.004	LIPT1, LIPT2
Metabolism of proteins	2	12.4×	0.007	LIPT1, LIPT2

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
protein lipoylation	2	1605.0×	3e-06	LIPT1, LIPT2
obsolete positive regulation of oxygen metabolic process	1	2808.7×	0.001	LIPT2
midbody abscission	1	244.2×	0.008	MITD1
negative regulation of protein binding	1	208.1×	0.008	MITD1
mitotic cytokinesis	1	86.4×	0.014	MITD1
protein modification process	1	81.4×	0.014	LIPT1
lipid metabolic process	1	30.5×	0.032	LIPT1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
LIPT1	0	0
LIPT2	0	0
MITD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LIPT2	2.3.1.181	lipoyl(octanoyl) transferase

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	1	LIPT2
E	Difficult family or no structure, no drug	2	LIPT1, MITD1

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)
LIPT1	0	—
LIPT2	0	—
MITD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.