Hypomyelinating leukodystrophy 3

Summary

Hypomyelinating leukodystrophy 3 (MONDO:0009843) is a disease caused by AIMP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: AIMP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 3
Mondo ID	MONDO:0009843
MeSH	C536319
OMIM	260600
Orphanet	280293
DOID	DOID:0060790
UMLS	C1850053
MedGen	342403
GARD	0004266
Is cancer (heuristic)	no

Also known as: AIMP1 leukodystrophy · HLD3 · hypomyelinating leukodystrophy 3 · hypomyelinating leukodystrophy type 3 · leukodystrophy caused by mutation in AIMP1 · leukodystrophy, hypomyelinating 3 · leukodystrophy, hypomyelinating, 3 · leukodystrophy, hypomyelinating, type 3 · Pelizaeus-Merzbacher-like disease due to AIMP1 mutation · perinatal Sudanophilic leukodystrophy

Data availability: 17 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › Pelizaeus-Merzbacher-like disease › hypomyelinating leukodystrophy 3

Related subtypes (2): hypomyelinating leukodystrophy 2, hypomyelinating leukodystrophy 4

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:

6 uncertain significance, 6 pathogenic, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
162377	NM_001142416.2(AIMP1):c.115C>T (p.Gln39Ter)	AIMP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2159413	NM_001142416.2(AIMP1):c.191_192del (p.Gln64fs)	AIMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
243083	NM_001142416.2(AIMP1):c.334C>T (p.Gln112Ter)	AIMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
30372	NM_001142416.2(AIMP1):c.292_293del (p.Gln98fs)	AIMP1	Pathogenic	no assertion criteria provided
3384795	NM_001142416.2(AIMP1):c.895G>A (p.Gly299Arg)	AIMP1	Pathogenic	criteria provided, single submitter
3589732	NM_001142416.2(AIMP1):c.267_282del (p.Asn89fs)	AIMP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776127	NM_001142416.2(AIMP1):c.695C>A (p.Ser232Ter)	AIMP1	Pathogenic	criteria provided, single submitter
590774	NM_001142416.2(AIMP1):c.162del (p.Lys54fs)	AIMP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3391194	NM_001142416.2(AIMP1):c.347del (p.Gly116fs)	AIMP1	Likely pathogenic	criteria provided, single submitter
4813746	NM_001142416.2(AIMP1):c.441_442insTT (p.Lys148fs)	AIMP1	Likely pathogenic	criteria provided, single submitter
1497296	NM_001142416.2(AIMP1):c.7AAT[1] (p.Asn4del)	AIMP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1676833	NM_001142416.2(AIMP1):c.223G>C (p.Val75Leu)	AIMP1	Uncertain significance	criteria provided, single submitter
2361483	NM_001142416.2(AIMP1):c.359A>G (p.Glu120Gly)	AIMP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438946	NM_001142416.2(AIMP1):c.800AGA[2] (p.Lys269del)	AIMP1	Uncertain significance	criteria provided, single submitter
2584934	NM_001142416.2(AIMP1):c.716T>C (p.Leu239Ser)	AIMP1	Uncertain significance	criteria provided, single submitter
4077875	NM_001142416.2(AIMP1):c.536T>G (p.Val179Gly)	AIMP1	Uncertain significance	criteria provided, single submitter
585142	NM_001142416.2(AIMP1):c.904A>G (p.Arg302Gly)	AIMP1	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
AIMP1	Strong	Autosomal recessive	hypomyelinating leukodystrophy 3	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AIMP1	Orphanet:280293	Pelizaeus-Merzbacher-like disease due to AIMP1 mutation
AIMP1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AIMP1	HGNC:10648	ENSG00000164022	Q12904	Aminoacyl tRNA synthase complex-interacting multifunctional protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIMP1	Aminoacyl tRNA synthase complex-interacting multifunctional protein 1	Non-catalytic component of the multisynthase complex.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AIMP1	Other/Unknown	no		tRNA-bd_dom, NA-bd_OB-fold,

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
rectum	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIMP1	295	ubiquitous	marker	calcaneal tendon, rectum, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIMP1	3,917

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIMP1	Q12904	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 1 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 tRNA aminoacylation	1	439.2×	0.014	AIMP1
tRNA Aminoacylation	1	285.5×	0.014	AIMP1
Selenoamino acid metabolism	1	196.9×	0.014	AIMP1
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.014	AIMP1
MITF-M-regulated melanocyte development	1	114.2×	0.018	AIMP1
Metabolism of amino acids and derivatives	1	67.6×	0.023	AIMP1
Translation	1	62.1×	0.023	AIMP1
Developmental Biology	1	14.5×	0.086	AIMP1
Metabolism of proteins	1	12.4×	0.086	AIMP1
Metabolism	1	11.6×	0.086	AIMP1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of glucagon secretion	1	8426.0×	0.001	AIMP1
leukocyte migration	1	624.1×	0.006	AIMP1
negative regulation of endothelial cell proliferation	1	543.6×	0.006	AIMP1
translation	1	102.8×	0.021	AIMP1
cell-cell signaling	1	69.6×	0.021	AIMP1
defense response to virus	1	69.3×	0.021	AIMP1
angiogenesis	1	62.4×	0.021	AIMP1
inflammatory response	1	37.7×	0.030	AIMP1
apoptotic process	1	28.7×	0.035	AIMP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AIMP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
AIMP1	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	1	AIMP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AIMP1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.