Leukodystrophy, hypomyelinating, 17

Summary

Leukodystrophy, hypomyelinating, 17 (MONDO:0054817) is a disease caused by AIMP2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: AIMP2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	leukodystrophy, hypomyelinating, 17
Mondo ID	MONDO:0054817
OMIM	618006
DOID	DOID:0070404
UMLS	C4693912
MedGen	1644557
GARD	0025980
Is cancer (heuristic)	no

Also known as: HLD17 · leukodystrophy, hypomyelinating, 17

Data availability: 9 ClinVar variants · 3 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 › leukodystrophy, hypomyelinating, 17

Related subtypes (64): Alexander disease, cerebrotendinous xanthomatosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, dermatoleukodystrophy, Krabbe disease, Sjogren-Larsson syndrome, Canavan disease, Pelizaeus-Merzbacher spectrum disorder, hereditary spastic paraplegia 2, megalencephalic leukoencephalopathy with subcortical cysts, ribose-5-P isomerase deficiency, hypomyelinating leukodystrophy 5, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, hypomyelinating leukodystrophy 6, cystic leukoencephalopathy without megalencephaly, sterol carrier protein 2 deficiency, leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome, hypomyelination with brain stem and spinal cord involvement and leg spasticity, leukoencephalopathy with mild cerebellar ataxia and white matter edema, progressive encephalopathy with leukodystrophy due to DECR deficiency, hypomyelinating leukodystrophy 9, multiple mitochondrial dysfunctions syndrome 4, hypomyelinating leukodystrophy 10, hypomyelinating leukodystrophy 12, hypomyelinating leukodystrophy 13, leukoencephalopathy with bilateral anterior temporal lobe cysts, progressive cavitating leukoencephalopathy, Pelizaeus-Merzbacher-like disease, CADDS, adrenoleukodystrophy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Aicardi-Goutieres syndrome, metachromatic leukodystrophy, peroxisome biogenesis disorder, unknown leukodystrophy, ravine syndrome, leukodystrophy, hypomyelinating, 22, leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy, neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination, leukodystrophy, hypomyelinating, 18, leukodystrophy, hypomyelinating, 19, transient infantile, spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, leukodystrophy, hypomyelinating, 14, leukodystrophy, hypomyelinating, 20, early-onset calcifying leukoencephalopathy-skeletal dysplasia, c11orf73-related autosomal recessive hypomyelinating leukodystrophy, alkaline ceramidase 3 deficiency, leukodystrophy, hypomyelinating, 15, leukodystrophy, hypomyelinating, 16, POLR-related leukodystrophy, leukoencephalopathy, diffuse hereditary, with spheroids 1, leukoencephalopathy with vanishing white matter, leukodystrophy, hypomyelinating, 24, leukodystrophy, childhood-onset, remitting, leukodystrophy, hypomyelinating, 25, leukodystrophy, hypomyelinating, 26, with chondrodysplasia, adult-onset progressive leukoencephalopathy-early-onset deafness, leukoencephalopathy, porphyria-related, episodic memory defect leukoencephalopathy, leukodystrophy, hypomyelinating, 28, leukodystrophy, demyelinating, adult-onset, leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy, leukoencephalopathy without lacunae, adult-onset, AARS1-related leukoencephalopathy

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

9 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 uncertain significance, 2 benign/likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
985778	NM_006303.4(AIMP2):c.72_73del (p.Met24fs)	AIMP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225106	NM_006303.4(AIMP2):c.575-2A>G	EIF2AK1	Pathogenic	criteria provided, multiple submitters, no conflicts
3062023	NM_006303.4(AIMP2):c.656_659del (p.Ser219fs)	AIMP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
428589	NM_006303.4(AIMP2):c.105C>A (p.Tyr35Ter)	AIMP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
982311	NM_006303.4(AIMP2):c.74A>G (p.Tyr25Cys)	AIMP2	Likely pathogenic	criteria provided, single submitter
2664220	NM_006303.4(AIMP2):c.135G>A (p.Gln45=)	AIMP2	Uncertain significance	criteria provided, single submitter
2441861	NM_006303.4(AIMP2):c.872G>A (p.Cys291Tyr)	EIF2AK1	Uncertain significance	criteria provided, single submitter
444713	NM_006303.4(AIMP2):c.16G>C (p.Val6Leu)	AIMP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
711475	NM_006303.4(AIMP2):c.462G>T (p.Thr154=)	AIMP2	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
AIMP2	Definitive	Autosomal recessive	leukodystrophy, hypomyelinating, 17	3

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
AIMP2	HGNC:20609	ENSG00000106305	Q13155	Aminoacyl tRNA synthase complex-interacting multifunctional protein 2	gencc,clinvar
EIF2AK1	HGNC:24921	ENSG00000086232	Q9BQI3	Eukaryotic translation initiation factor 2-alpha kinase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AIMP2	Aminoacyl tRNA synthase complex-interacting multifunctional protein 2	Required for assembly and stability of the aminoacyl-tRNA synthase complex.
EIF2AK1	Eukaryotic translation initiation factor 2-alpha kinase 1	Metabolic-stress sensing protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) in response to various stress conditions.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AIMP2	Other/Unknown	no		GST_C, AIMP2_LysRS-bd, Glutathione-S-Trfase_C_sf
EIF2AK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

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
oocyte	1
secondary oocyte	1
vastus lateralis	1
monocyte	1
mononuclear cell	1
trabecular bone tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AIMP2	297	ubiquitous	marker	oocyte, secondary oocyte, vastus lateralis
EIF2AK1	289	ubiquitous	marker	trabecular bone tissue, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AIMP2	2,867
EIF2AK1	2,006

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIMP2	Q13155	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EIF2AK1	Q9BQI3	64.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 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
Cellular response to mitochondrial stress	1	571.0×	0.017	EIF2AK1
Response of EIF2AK1 (HRI) to heme deficiency	1	356.9×	0.017	EIF2AK1
Cytosolic tRNA aminoacylation	1	219.6×	0.018	AIMP2
tRNA Aminoacylation	1	142.8×	0.021	AIMP2
Selenoamino acid metabolism	1	98.5×	0.022	AIMP2
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.022	AIMP2
MITF-M-regulated melanocyte development	1	57.1×	0.030	AIMP2
Metabolism of amino acids and derivatives	1	33.8×	0.043	AIMP2
Translation	1	31.0×	0.043	AIMP2
Developmental Biology	1	7.2×	0.160	AIMP2
Metabolism of proteins	1	6.2×	0.165	AIMP2
Metabolism	1	5.8×	0.165	AIMP2

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
negative regulation of translational initiation by iron	1	8426.0×	0.001	EIF2AK1
negative regulation of hemoglobin biosynthetic process	1	8426.0×	0.001	EIF2AK1
obsolete protoporphyrinogen IX metabolic process	1	4213.0×	0.002	EIF2AK1
response to iron ion starvation	1	2808.7×	0.002	EIF2AK1
negative regulation of cell population proliferation	2	42.1×	0.003	AIMP2, EIF2AK1
type II pneumocyte differentiation	1	1053.2×	0.003	AIMP2
HRI-mediated signaling	1	1053.2×	0.003	EIF2AK1
acute inflammatory response	1	842.6×	0.003	EIF2AK1
protein localization to mitochondrion	1	648.1×	0.004	EIF2AK1
positive regulation of mitophagy	1	561.7×	0.004	EIF2AK1
integrated stress response signaling	1	351.1×	0.006	EIF2AK1
multicellular organismal-level iron ion homeostasis	1	290.6×	0.007	EIF2AK1
regulation of translational initiation	1	234.1×	0.007	EIF2AK1
macrophage differentiation	1	234.1×	0.007	EIF2AK1
positive regulation of neuron apoptotic process	1	135.9×	0.011	AIMP2
phagocytosis	1	120.4×	0.012	EIF2AK1
positive regulation of protein ubiquitination	1	106.7×	0.013	AIMP2
establishment of localization in cell	1	80.2×	0.016	EIF2AK1
protein autophosphorylation	1	72.6×	0.017	EIF2AK1
protein-containing complex assembly	1	56.9×	0.020	AIMP2
translation	1	51.4×	0.021	AIMP2
protein ubiquitination	1	20.7×	0.050	AIMP2
apoptotic process	1	14.3×	0.068	AIMP2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
EIF2AK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2AK1	17	4
AIMP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	EIF2AK1
DABRAFENIB	4	EIF2AK1
BARICITINIB	4	EIF2AK1
BOSUTINIB	4	EIF2AK1
ABEMACICLIB	4	EIF2AK1
MIDOSTAURIN	4	EIF2AK1
ALVOCIDIB	3	EIF2AK1
CEDIRANIB	3	EIF2AK1
SILMITASERTIB	2	EIF2AK1
FORETINIB	2	EIF2AK1
REBASTINIB	2	EIF2AK1
DEFOSBARASERTIB	2	EIF2AK1
OSI-632	2	EIF2AK1
GOLVATINIB	2	EIF2AK1
AZD-8330	1	EIF2AK1
RGB-286638	1	EIF2AK1
XL-228	1	EIF2AK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EIF2AK1	124	Binding:124
AIMP2	23	Binding:21, ADMET:2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EIF2AK1	124

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

17 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.

Compound	Max phase	Cohort target (bioactivity)
FEDRATINIB	4	EIF2AK1
DABRAFENIB	4	EIF2AK1
BARICITINIB	4	EIF2AK1
BOSUTINIB	4	EIF2AK1
ABEMACICLIB	4	EIF2AK1
MIDOSTAURIN	4	EIF2AK1
ALVOCIDIB	3	EIF2AK1
CEDIRANIB	3	EIF2AK1
SILMITASERTIB	2	EIF2AK1
FORETINIB	2	EIF2AK1
REBASTINIB	2	EIF2AK1
DEFOSBARASERTIB	2	EIF2AK1
OSI-632	2	EIF2AK1
GOLVATINIB	2	EIF2AK1
AZD-8330	1	EIF2AK1
RGB-286638	1	EIF2AK1
XL-228	1	EIF2AK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EIF2AK1
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	AIMP2

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)
AIMP2	23	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.