POLR-related leukodystrophy

Summary

POLR-related leukodystrophy (MONDO:0100605) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 17
• Phenotypes (HPO): 32

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

32 HPO clinical features (Orphanet curated; top 32 by frequency):

HPO ID	Term	Frequency
HP:0000044	Hypogonadotropic hypogonadism	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0000668	Hypodontia	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001260	Dysarthria	Very frequent (80-99%)
HP:0001332	Dystonia	Very frequent (80-99%)
HP:0006808	Cerebral hypomyelination	Very frequent (80-99%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000823	Delayed puberty	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002493	Upper motor neuron dysfunction	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007240	Progressive gait ataxia	Frequent (30-79%)
HP:0030890	Hyperintensity of cerebral white matter on MRI	Frequent (30-79%)
HP:0000570	Abnormal saccadic eye movements	Occasional (5-29%)
HP:0000640	Gaze-evoked nystagmus	Occasional (5-29%)
HP:0000684	Delayed eruption of teeth	Occasional (5-29%)
HP:0000824	Decreased response to growth hormone stimulation test	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001310	Dysmetria	Occasional (5-29%)
HP:0002075	Dysdiadochokinesis	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002926	Abnormality of thyroid physiology	Occasional (5-29%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000648	Optic atrophy	Very rare (<1-4%)
HP:0031206	Striatal T2 hyperintensity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	POLR-related leukodystrophy
Mondo ID	MONDO:0100605
Orphanet	289494
UMLS	C5679947
MedGen	1803536
GARD	0027288
Is cancer (heuristic)	no

Also known as: 4H leukodystrophy

Data availability: 17 ClinVar variants · 7 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › leukodystrophy › POLR-related leukodystrophy

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, leukodystrophy, hypomyelinating, 17, 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

Subtypes (2): POLR3-related leukodystrophy, leukodystrophy, hypomyelinating, 27

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 pathogenic/likely pathogenic, 5 pathogenic, 3 uncertain significance, 3 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
560463	NM_000180.4(GUCY2D):c.2303G>A (p.Arg768Gln)	GUCY2D	Pathogenic	reviewed by expert panel
1903818	NM_007055.4(POLR3A):c.3951dup (p.Leu1318fs)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
2691390	NC_000010.10:g.(79779024_79781303)_(79782143_79784306)del	POLR3A	Pathogenic	criteria provided, single submitter
31143	NM_007055.4(POLR3A):c.2015G>A (p.Gly672Glu)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366589	NM_007055.4(POLR3A):c.2100del (p.Ile700fs)	POLR3A	Pathogenic	criteria provided, single submitter
445922	NM_007055.4(POLR3A):c.1909+22G>A	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449556	NM_007055.4(POLR3A):c.1771-7C>G	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
617894	NM_007055.4(POLR3A):c.760C>T (p.Arg254Ter)	POLR3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
684774	NM_007055.4(POLR3A):c.601del (p.Ile201fs)	POLR3A	Pathogenic	criteria provided, multiple submitters, no conflicts
1069879	NM_018082.6(POLR3B):c.2413C>T (p.Arg805Ter)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31166	NM_018082.6(POLR3B):c.1568T>A (p.Val523Glu)	POLR3B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
285205	NM_018082.6(POLR3B):c.1244T>C (p.Met415Thr)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
31161	NM_018082.6(POLR3B):c.2303G>A (p.Arg768His)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873511	NM_018082.6(POLR3B):c.2278G>A (p.Ala760Thr)	POLR3B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2637961	NM_018082.6(POLR3B):c.2974G>A (p.Gly992Ser)	LOC100287944	Uncertain significance	criteria provided, single submitter
989354	NM_018082.6(POLR3B):c.478G>A (p.Glu160Lys)	POLR3B	Uncertain significance	criteria provided, multiple submitters, no conflicts
989355	NM_018082.6(POLR3B):c.1121A>G (p.Glu374Gly)	POLR3B	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
POLR3B	Orphanet:85186	Endosteal sclerosis-cerebellar hypoplasia syndrome
POLR3B	Orphanet:88637	Hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome
GUCY2D	Orphanet:1872	Cone rod dystrophy
GUCY2D	Orphanet:65	Leber congenital amaurosis
GUCY2D	Orphanet:75377	Central areolar choroidal dystrophy

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
POLR3A	HGNC:30074	ENSG00000148606	O14802	DNA-directed RNA polymerase III subunit RPC1	clinvar
POLR3B	HGNC:30348	ENSG00000013503	Q9NW08	DNA-directed RNA polymerase III subunit RPC2	clinvar
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
POLR3B	DNA-directed RNA polymerase III subunit RPC2	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.
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.

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
Kinase	1	9.2×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLR3A	Other/Unknown	no		RNA_pol_asu, RNA_pol_N, RNA_pol_Rpb1_3
POLR3B	Other/Unknown	no		DNA-dir_RNAP_su2_dom, RNA_pol_bsu_CS, RNA_pol_Rpb2_7
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	2
secondary oocyte	2
middle temporal gyrus	1
endothelial cell	1
esophagus squamous epithelium	1
esophagus mucosa	1
lower esophagus mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLR3A	242	ubiquitous	marker	buccal mucosa cell, middle temporal gyrus, secondary oocyte
POLR3B	247	ubiquitous	marker	secondary oocyte, esophagus squamous epithelium, endothelial cell
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLR3B	5,712
POLR3A	4,915
GUCY2D	1,083

Intra-cohort edges

A	B	Sources
POLR3A	POLR3B	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3A	O14802	29
POLR3B	Q9NW08	29

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GUCY2D	Q02846	82.37

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RNA Polymerase III Chain Elongation	2	423.0×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Termination	2	331.0×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 2 Promoter	2	282.0×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 1 Promoter	2	271.9×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation From Type 3 Promoter	2	271.9×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription Initiation	2	223.9×	5e-05	POLR3A, POLR3B
RNA Polymerase III Transcription	2	217.5×	5e-05	POLR3A, POLR3B
Cytosolic sensors of pathogen-associated DNA	2	190.3×	5e-05	POLR3A, POLR3B
RNA Polymerase III Abortive And Retractive Initiation	2	185.7×	5e-05	POLR3A, POLR3B
Innate Immune System	2	17.0×	0.006	POLR3A, POLR3B
Inactivation, recovery and regulation of the phototransduction cascade	1	105.7×	0.010	GUCY2D
Gene expression (Transcription)	2	11.9×	0.010	POLR3A, POLR3B
Immune System	2	8.6×	0.017	POLR3A, POLR3B

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
positive regulation of interferon-beta production	2	261.3×	2e-04	POLR3A, POLR3B
defense response to virus	2	46.2×	0.004	POLR3A, POLR3B
snRNA transcription by RNA polymerase III	1	624.1×	0.004	POLR3B
regulation of opsin-mediated signaling pathway	1	561.7×	0.004	GUCY2D
tRNA transcription by RNA polymerase III	1	510.7×	0.004	POLR3A
cGMP biosynthetic process	1	468.1×	0.004	GUCY2D
receptor guanylyl cyclase signaling pathway	1	432.1×	0.004	GUCY2D
innate immune response	2	22.4×	0.004	POLR3A, POLR3B
obsolete cGMP-mediated signaling	1	267.5×	0.005	GUCY2D
positive regulation of innate immune response	1	175.5×	0.007	POLR3B
DNA-templated transcription	1	74.9×	0.015	POLR3A
visual perception	1	26.5×	0.037	GUCY2D

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLR3A	0	0
POLR3B	0	0
GUCY2D	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GUCY2D	4.6.1.2	guanylate cyclase

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	GUCY2D
E	Difficult family or no structure, no drug	2	POLR3A, POLR3B

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)
POLR3A	0	—
POLR3B	0	—
GUCY2D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.