Hypomyelinating leukodystrophy 4

Summary

Hypomyelinating leukodystrophy 4 (MONDO:0012824) is a disease caused by HSPD1 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: HSPD1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 18

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypomyelinating leukodystrophy 4
Mondo ID	MONDO:0012824
MeSH	C567390
OMIM	612233
Orphanet	280288
DOID	DOID:0060789
UMLS	C2677109
MedGen	383026
GARD	0017294
Is cancer (heuristic)	no

Also known as: HLD4 · HSPD1 leukodystrophy · hypomyelinating leukodystrophy type 4 · leukodystrophy caused by mutation in HSPD1 · leukodystrophy, hypomyelinating, 4 · leukodystrophy, hypomyelinating, type 4 · MitCHAP60 disease · mitochondrial HSP60 chaperonopathy · Pelizaeus-Merzbacher-like disease due to HSPD1 mutation

Data availability: 18 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 4

Related subtypes (2): hypomyelinating leukodystrophy 3, hypomyelinating leukodystrophy 2

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

18 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
17558	NM_002156.5(HSPD1):c.86A>G (p.Asp29Gly)	HSPD1	Pathogenic	criteria provided, single submitter
3767209	NM_002156.5(HSPD1):c.185T>C (p.Val62Ala)	HSPD1	Likely pathogenic	criteria provided, single submitter
816623	NM_002156.5(HSPD1):c.139T>G (p.Leu47Val)	HSPD1	Likely pathogenic	no assertion criteria provided
590969	NM_007055.4(POLR3A):c.2471A>C (p.His824Pro)	POLR3A	Likely pathogenic	criteria provided, single submitter
410974	NM_002156.5(HSPD1):c.871C>G (p.Leu291Val)	HSPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410975	NM_002156.5(HSPD1):c.1712G>T (p.Gly571Val)	HSPD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029563	NM_002156.5(HSPD1):c.947T>C (p.Met316Thr)	HSPD1	Uncertain significance	criteria provided, single submitter
1440407	NM_002156.5(HSPD1):c.445G>C (p.Asp149His)	HSPD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1705500	NM_002156.5(HSPD1):c.1257C>A (p.Asp419Glu)	HSPD1	Uncertain significance	criteria provided, single submitter
2693833	NM_002156.5(HSPD1):c.1462T>A (p.Ser488Thr)	HSPD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3391384	NM_002156.5(HSPD1):c.386A>G (p.Glu129Gly)	HSPD1	Uncertain significance	criteria provided, single submitter
3391391	NM_002156.5(HSPD1):c.1151A>C (p.Glu384Ala)	HSPD1	Uncertain significance	criteria provided, single submitter
3585124	NM_002156.5(HSPD1):c.299A>T (p.Asp100Val)	HSPD1	Uncertain significance	criteria provided, single submitter
4279831	NM_002156.5(HSPD1):c.1169T>C (p.Leu390Pro)	HSPD1	Uncertain significance	criteria provided, single submitter
976190	NM_002156.5(HSPD1):c.1394_1406del (p.Ile465fs)	HSPD1	Uncertain significance	criteria provided, single submitter
129241	NM_002156.5(HSPD1):c.273A>G (p.Lys91=)	HSPD1	Benign	criteria provided, multiple submitters, no conflicts
214549	NM_002156.5(HSPD1):c.561T>C (p.Ser187=)	HSPD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
800207	NM_002156.5(HSPD1):c.1681A>G (p.Met561Val)	HSPD1	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
HSPD1	Strong	Autosomal recessive	hypomyelinating leukodystrophy 4	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HSPD1	Orphanet:100994	Autosomal dominant spastic paraplegia type 13
HSPD1	Orphanet:280288	Pelizaeus-Merzbacher-like disease due to HSPD1 mutation
POLR3A	Orphanet:137639	Hypomyelinating leukodystrophy-ataxia-hypodontia-hypomyelination syndrome
POLR3A	Orphanet:3455	Wiedemann-Rautenstrauch syndrome
POLR3A	Orphanet:447893	Hypomyelination-cerebellar atrophy-hypoplasia of the corpus callosum syndrome
POLR3A	Orphanet:447896	Tremor-ataxia-central hypomyelination syndrome
POLR3A	Orphanet:77295	Odontoleukodystrophy
POLR3A	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

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
HSPD1	HGNC:5261	ENSG00000144381	P10809	60 kDa heat shock protein, mitochondrial	gencc,clinvar
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HSPD1	60 kDa heat shock protein, mitochondrial	Chaperonin implicated in mitochondrial protein import and macromolecular assembly.
POLR3A	DNA-directed RNA polymerase III subunit RPC1	Catalytic core component of RNA polymerase III (Pol III), a DNA-dependent RNA polymerase which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HSPD1	Other/Unknown	no		Cpn60/GroEL, Cpn60/GroEL/TCP-1, Chaperonin_Cpn60_CS
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3

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
adrenal tissue	1
right adrenal gland	1
right adrenal gland cortex	1
buccal mucosa cell	1
middle temporal gyrus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HSPD1	217	ubiquitous	marker	adrenal tissue, right adrenal gland, right adrenal gland cortex
POLR3A	242	ubiquitous	marker	buccal mucosa cell, middle temporal gyrus, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPD1	7,876
POLR3A	4,915

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSPD1	P10809	31
POLR3A	O14802	29

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	1142.0×	0.010	HSPD1
RNA Polymerase III Chain Elongation	1	317.2×	0.010	POLR3A
Mitochondrial unfolded protein response (UPRmt)	1	300.5×	0.010	HSPD1
RNA Polymerase III Transcription Termination	1	248.3×	0.010	POLR3A
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.010	POLR3A
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.010	POLR3A
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.010	POLR3A
RNA Polymerase III Transcription Initiation	1	167.9×	0.010	POLR3A
RNA Polymerase III Transcription	1	163.1×	0.010	POLR3A
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.010	POLR3A
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.010	POLR3A
Mitochondrial protein import	1	84.0×	0.016	HSPD1
Mitochondrial protein degradation	1	57.1×	0.021	HSPD1
Innate Immune System	1	12.8×	0.088	POLR3A
Gene expression (Transcription)	1	8.9×	0.116	POLR3A
Immune System	1	6.5×	0.148	POLR3A

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
isotype switching to IgG isotypes	1	8426.0×	0.004	HSPD1
mitochondrial unfolded protein response	1	4213.0×	0.004	HSPD1
protein import into mitochondrial intermembrane space	1	2808.7×	0.004	HSPD1
‘de novo’ protein folding	1	2106.5×	0.004	HSPD1
biological process involved in interaction with symbiont	1	1404.3×	0.004	HSPD1
positive regulation of T cell mediated immune response to tumor cell	1	1203.7×	0.004	HSPD1
negative regulation of execution phase of apoptosis	1	1203.7×	0.004	HSPD1
tRNA transcription by RNA polymerase III	1	766.0×	0.006	POLR3A
cellular response to interleukin-7	1	648.1×	0.006	HSPD1
MyD88-dependent toll-like receptor signaling pathway	1	468.1×	0.006	HSPD1
apoptotic mitochondrial changes	1	443.5×	0.006	HSPD1
positive regulation of macrophage activation	1	421.3×	0.006	HSPD1
positive regulation of execution phase of apoptosis	1	421.3×	0.006	HSPD1
chaperone-mediated protein complex assembly	1	351.1×	0.007	HSPD1
positive regulation of interferon-alpha production	1	324.1×	0.007	HSPD1
protein refolding	1	312.1×	0.007	HSPD1
response to cold	1	280.9×	0.007	HSPD1
B cell proliferation	1	240.7×	0.008	HSPD1
B cell activation	1	227.7×	0.008	HSPD1
positive regulation of T cell activation	1	221.7×	0.008	HSPD1
positive regulation of interleukin-10 production	1	200.6×	0.008	HSPD1
positive regulation of interferon-beta production	1	195.9×	0.008	POLR3A
positive regulation of interleukin-12 production	1	195.9×	0.008	HSPD1
response to unfolded protein	1	150.5×	0.009	HSPD1
T cell activation	1	129.6×	0.010	HSPD1
DNA-templated transcription	1	112.3×	0.011	POLR3A
positive regulation of type II interferon production	1	112.3×	0.011	HSPD1
positive regulation of interleukin-6 production	1	83.4×	0.014	HSPD1
protein maturation	1	81.8×	0.014	HSPD1
protein folding	1	51.7×	0.022	HSPD1

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
HSPD1	CHOLECALCIFEROL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HSPD1	27	4
POLR3A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CHOLECALCIFEROL	4	HSPD1
EVANS BLUE	4	HSPD1
PHENOXYBENZAMINE HYDROCHLORIDE	4	HSPD1
ADAPALENE	4	HSPD1
ERGOCALCIFEROL	4	HSPD1
METABROMSALAN	4	HSPD1
BITHIONOL	4	HSPD1
TRETINOIN	4	HSPD1
BENZBROMARONE	4	HSPD1
RIBOFLAVIN 5’-PHOSPHATE SODIUM	4	HSPD1
ETHACRYNIC ACID	4	HSPD1
HEXACHLOROPHENE	4	HSPD1
TANNIC ACID	4	HSPD1
MENADIONE	4	HSPD1
IVERMECTIN	4	HSPD1
GENTIAN VIOLET	4	HSPD1
MESALAMINE	4	HSPD1
CURCUMIN	3	HSPD1
CETYLPYRIDINIUM CHLORIDE	3	HSPD1
SURAMIN	3	HSPD1
EPIGALOCATECHIN GALLATE	3	HSPD1
CLOSANTEL	2	HSPD1
LAPACHONE	2	HSPD1
BENZETHONIUM CHLORIDE	2	HSPD1
RAFOXANIDE	2	HSPD1
DICHLOROPHEN	2	HSPD1
PLUMBAGIN	1	HSPD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HSPD1	22	Binding:18, ADMET:2, Functional:2

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

27 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)
CHOLECALCIFEROL	4	HSPD1
EVANS BLUE	4	HSPD1
PHENOXYBENZAMINE HYDROCHLORIDE	4	HSPD1
ADAPALENE	4	HSPD1
ERGOCALCIFEROL	4	HSPD1
METABROMSALAN	4	HSPD1
BITHIONOL	4	HSPD1
TRETINOIN	4	HSPD1
BENZBROMARONE	4	HSPD1
RIBOFLAVIN 5’-PHOSPHATE SODIUM	4	HSPD1
ETHACRYNIC ACID	4	HSPD1
HEXACHLOROPHENE	4	HSPD1
TANNIC ACID	4	HSPD1
MENADIONE	4	HSPD1
IVERMECTIN	4	HSPD1
GENTIAN VIOLET	4	HSPD1
MESALAMINE	4	HSPD1
CURCUMIN	3	HSPD1
CETYLPYRIDINIUM CHLORIDE	3	HSPD1
SURAMIN	3	HSPD1
EPIGALOCATECHIN GALLATE	3	HSPD1
CLOSANTEL	2	HSPD1
LAPACHONE	2	HSPD1
BENZETHONIUM CHLORIDE	2	HSPD1
RAFOXANIDE	2	HSPD1
DICHLOROPHEN	2	HSPD1
PLUMBAGIN	1	HSPD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HSPD1
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	POLR3A

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)
POLR3A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.