peroxisome biogenesis disorder 1A (Zellweger)

Summary

peroxisome biogenesis disorder 1A (Zellweger) (MONDO:0008953) is a disease caused by PEX1 (GenCC Definitive), with 9 cohort genes. The dominant Reactome pathway is Peroxisomal protein import (5 cohort genes).

At a glance

• Causal gene: PEX1 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 387

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 1A (Zellweger)
Mondo ID	MONDO:0008953
OMIM	214100
DOID	DOID:0080476
UMLS	C4721541
MedGen	1648474
GARD	0024644
Is cancer (heuristic)	no

Also known as: PBD1A · peroxisome biogenesis disorder 1A (Zellweger)

Data availability: 387 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › Zellweger spectrum disorders › peroxisome biogenesis disorder due to PEX1 defect › peroxisome biogenesis disorder 1A (Zellweger)

Related subtypes (1): peroxisome biogenesis disorder 1B

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

387 retrieved; paginated sample, class counts are floors:

114 likely pathogenic, 82 uncertain significance, 60 pathogenic/likely pathogenic, 59 conflicting classifications of pathogenicity, 46 pathogenic, 14 benign/likely benign, 11 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1252072	NM_000466.3(PEX1):c.3568C>T (p.Gln1190Ter)	GATAD1	Pathogenic	no assertion criteria provided
1726581	NM_000466.3(PEX1):c.3258_3261del (p.Phe1086fs)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188729	NM_000466.3(PEX1):c.2926+1G>A	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189002	NM_000466.3(PEX1):c.2926+2T>C	GATAD1	Pathogenic	criteria provided, multiple submitters, no conflicts
203390	NM_000466.3(PEX1):c.3379dup (p.Arg1127fs)	GATAD1	Pathogenic	no assertion criteria provided
287046	NM_000466.3(PEX1):c.3303_3304dup (p.Cys1102fs)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371696	NM_000466.3(PEX1):c.2922del (p.Leu974fs)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371698	NM_000466.3(PEX1):c.3574C>T (p.Gln1192Ter)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371765	NM_000466.3(PEX1):c.3208-1G>A	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371774	NM_000466.3(PEX1):c.3455_3456del (p.Ser1152fs)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495880	NM_000466.3(PEX1):c.2992C>T (p.Arg998Ter)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
528228	NC_000007.14:g.(?92489273)(92491522_?)del	GATAD1	Pathogenic	criteria provided, single submitter
551650	NM_000466.3(PEX1):c.3038G>A (p.Arg1013His)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
556176	NM_000466.3(PEX1):c.2846G>A (p.Arg949Gln)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
591802	NM_000466.3(PEX1):c.3115del (p.Thr1039fs)	GATAD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451521	NM_000466.3(PEX1):c.56_80del (p.Val19fs)	LOC129998796	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371688	NM_000466.3(PEX1):c.2T>G (p.Met1Arg)	LOC129998796	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371744	NM_000466.3(PEX1):c.1A>T (p.Met1Leu)	LOC129998796	Pathogenic	criteria provided, multiple submitters, no conflicts
552166	NM_000466.3(PEX1):c.1A>C (p.Met1Leu)	LOC129998796	Pathogenic	criteria provided, multiple submitters, no conflicts
558040	NM_000466.3(PEX1):c.5G>A (p.Trp2Ter)	LOC129998796	Pathogenic	criteria provided, multiple submitters, no conflicts
1069047	NM_000466.3(PEX1):c.3037C>T (p.Arg1013Cys)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098815	NM_000466.3(PEX1):c.130-2A>T	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1252071	NM_000466.3(PEX1):c.1240_1359del (p.Ile414_Leu453del)	PEX1	Pathogenic	no assertion criteria provided
1324877	NM_000466.3(PEX1):c.1099del (p.Gln367fs)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363179	NM_000466.3(PEX1):c.3152_3156del (p.Leu1051fs)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1442533	NM_000466.3(PEX1):c.538_541dup (p.Thr181fs)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453236	NM_000466.3(PEX1):c.3622del (p.Arg1208fs)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457878	NM_000466.3(PEX1):c.831_834del (p.Ser278fs)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1495205	NM_000466.3(PEX1):c.357+1G>T	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1726455	NM_000466.3(PEX1):c.205C>T (p.Gln69Ter)	PEX1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 28 · 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
PEX1	Definitive	Autosomal recessive	peroxisome biogenesis disorder 1A (Zellweger)	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PEX1	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX1	Orphanet:44	Neonatal adrenoleukodystrophy
PEX1	Orphanet:772	Infantile Refsum disease
PEX1	Orphanet:912	Zellweger syndrome
PEX26	Orphanet:44	Neonatal adrenoleukodystrophy
PEX26	Orphanet:772	Infantile Refsum disease
PEX26	Orphanet:912	Zellweger syndrome
GATAD1	Orphanet:154	Familial isolated dilated cardiomyopathy
PEX16	Orphanet:44	Neonatal adrenoleukodystrophy
PEX16	Orphanet:642954	Autosomal recessive ataxia due to PEX16 deficiency
PEX16	Orphanet:772	Infantile Refsum disease
PEX16	Orphanet:912	Zellweger syndrome
PEX3	Orphanet:44	Neonatal adrenoleukodystrophy
PEX3	Orphanet:772	Infantile Refsum disease
PEX3	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome
PEX2	Orphanet:44	Neonatal adrenoleukodystrophy
PEX2	Orphanet:642965	Autosomal recessive ataxia due to PEX2 deficiency
PEX2	Orphanet:772	Infantile Refsum disease
PEX2	Orphanet:912	Zellweger syndrome
PEX5	Orphanet:44	Neonatal adrenoleukodystrophy
PEX5	Orphanet:468717	Rhizomelic chondrodysplasia punctata type 5
PEX5	Orphanet:772	Infantile Refsum disease
PEX5	Orphanet:912	Zellweger syndrome

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PEX1	HGNC:8850	ENSG00000127980	O43933	Peroxisomal ATPase PEX1	gencc,clinvar
PEX26	HGNC:22965	ENSG00000215193	Q7Z412	Peroxisome assembly protein 26	clinvar
PAF1	HGNC:25459	ENSG00000006712	Q8N7H5	RNA polymerase II-associated factor 1 homolog	clinvar
GATAD1	HGNC:29941	ENSG00000157259	Q8WUU5	GATA zinc finger domain-containing protein 1	clinvar
PEX16	HGNC:8857	ENSG00000121680	Q9Y5Y5	Peroxisomal membrane protein PEX16	clinvar
PEX3	HGNC:8858	ENSG00000034693	P56589	Peroxisomal biogenesis factor 3	clinvar
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	clinvar
PEX2	HGNC:9717	ENSG00000164751	P28328	Peroxisome biogenesis factor 2	clinvar
PEX5	HGNC:9719	ENSG00000139197	P50542	Peroxisomal targeting signal 1 receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PEX1	Peroxisomal ATPase PEX1	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.
PEX26	Peroxisome assembly protein 26	Peroxisomal docking factor that anchors PEX1 and PEX6 to peroxisome membranes.
PAF1	RNA polymerase II-associated factor 1 homolog	Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency.
GATAD1	GATA zinc finger domain-containing protein 1	Component of some chromatin complex recruited to chromatin sites methylated ‘Lys-4’ of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3).
PEX16	Peroxisomal membrane protein PEX16	Required for peroxisome membrane biogenesis.
PEX3	Peroxisomal biogenesis factor 3	Involved in peroxisome biosynthesis and integrity.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.
PEX2	Peroxisome biogenesis factor 2	E3 ubiquitin-protein ligase component of a retrotranslocation channel required for peroxisome organization by mediating export of the PEX5 receptor from peroxisomes to the cytosol, thereby promoting PEX5 recycling.
PEX5	Peroxisomal targeting signal 1 receptor	Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type).

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.22

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)	2	2.7×	0.449
Transcription factor	2	1.8×	0.449
Other/Unknown	5	1.0×	0.641

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX1	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
PEX26	Other/Unknown	no		Pex26
PAF1	Other/Unknown	no		RNA_pol_II-assoc_Paf1
GATAD1	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, GATAD1
PEX16	Other/Unknown	no		Pex16
PEX3	Other/Unknown	no		Peroxin-3
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
PEX2	Transcription factor	no		Znf_RING, Pex_N, Znf_RING/FYVE/PHD
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	2
mucosa of transverse colon	2
tendon of biceps brachii	2
left testis	2
right uterine tube	2
calcaneal tendon	1
mucosa of stomach	1
cortical plate	1
sural nerve	1
inferior vagus X ganglion	1
left ovary	1
granulocyte	1
prefrontal cortex	1
right lobe of liver	1
adrenal tissue	1
endothelial cell	1
right adrenal gland cortex	1
olfactory segment of nasal mucosa	1
seminal vesicle	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX1	279	ubiquitous	marker	calcaneal tendon, body of pancreas, mucosa of stomach
PEX26	253	ubiquitous	marker	mucosa of transverse colon, tendon of biceps brachii, cortical plate
PAF1	296	ubiquitous	marker	tendon of biceps brachii, sural nerve, left testis
GATAD1	287	ubiquitous	marker	left ovary, right uterine tube, inferior vagus X ganglion
PEX16	281	ubiquitous	marker	prefrontal cortex, granulocyte, right lobe of liver
PEX3	291	ubiquitous	marker	adrenal tissue, endothelial cell, right adrenal gland cortex
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon
PEX2	291	ubiquitous	marker	seminal vesicle, ventricular zone, olfactory segment of nasal mucosa
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX6	2,620
PEX1	2,413
PAF1	2,106
PEX3	1,838
PEX5	1,741
PEX16	1,231
GATAD1	1,065
PEX2	1,018
PEX26	775

Intra-cohort edges

A	B	Sources
PEX1	PEX16	string_interaction
PEX1	PEX2	string_interaction
PEX1	PEX26	biogrid_interaction, string_interaction
PEX1	PEX3	string_interaction
PEX1	PEX5	string_interaction
PEX1	PEX6	biogrid_interaction, intact
PEX16	PEX2	string_interaction
PEX16	PEX26	string_interaction
PEX16	PEX3	biogrid_interaction, intact, string_interaction
PEX16	PEX5	string_interaction
PEX16	PEX6	string_interaction
PEX2	PEX26	string_interaction
PEX2	PEX3	string_interaction
PEX2	PEX5	intact, string_interaction
PEX2	PEX6	string_interaction
PEX26	PEX3	intact, string_interaction
PEX26	PEX5	string_interaction
PEX26	PEX6	biogrid_interaction, string_interaction
PEX3	PEX5	string_interaction
PEX3	PEX6	string_interaction
PEX5	PEX6	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAF1	Q8N7H5	21
PEX5	P50542	11
PEX3	P56589	2
GATAD1	Q8WUU5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX16	Q9Y5Y5	83.07
PEX2	P28328	81.17
PEX26	Q7Z412	79.87
PEX6	Q13608	69.87
PEX1	O43933	67.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Peroxisomal protein import	5	108.1×	3e-09	PEX1, PEX26, PEX6, PEX2, PEX5
Class I peroxisomal membrane protein import	4	259.6×	4e-09	PEX26, PEX16, PEX3, PEX2
E3 ubiquitin ligases ubiquitinate target proteins	3	72.6×	2e-05	PAF1, PEX2, PEX5
Pexophagy	1	119.0×	0.021	PEX5
ABC transporters in lipid homeostasis	1	75.1×	0.026	PEX3
Dengue virus activates/modulates innate and adaptive immune responses	1	42.0×	0.039	PAF1
Formation of RNA Pol II elongation complex	1	24.2×	0.051	PAF1
RNA Polymerase II Transcription Elongation	1	24.2×	0.051	PAF1
RNA Polymerase II Pre-transcription Events	1	17.2×	0.063	PAF1
CHD1 and CHD2 subfamily	1	13.6×	0.071	PAF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein import into peroxisome matrix	6	936.2×	1e-16	PEX1, PEX26, PEX16, PEX6, PEX2, PEX5
peroxisome organization	5	445.8×	5e-12	PEX1, PEX16, PEX3, PEX6, PEX2
protein import into peroxisome membrane	4	1248.3×	9e-12	PEX26, PEX16, PEX3, PEX5
protein import into peroxisome matrix, receptor recycling	4	1070.0×	2e-11	PEX1, PEX6, PEX2, PEX5
protein targeting to peroxisome	4	749.0×	8e-11	PEX1, PEX16, PEX6, PEX5
protein import into peroxisome matrix, translocation	2	936.2×	1e-05	PEX6, PEX5
protein to membrane docking	2	749.0×	1e-05	PEX26, PEX16
protein unfolding	2	749.0×	1e-05	PEX1, PEX6
protein import into peroxisome matrix, substrate release	2	749.0×	1e-05	PEX2, PEX5
pexophagy	2	234.1×	1e-04	PEX2, PEX5
very long-chain fatty acid metabolic process	2	170.2×	3e-04	PEX2, PEX5
cellular response to reactive oxygen species	2	91.3×	8e-04	PEX2, PEX5
fatty acid beta-oxidation	2	83.2×	9e-04	PEX2, PEX5
ER-dependent peroxisome organization	1	1872.4×	0.002	PEX16
ER-dependent peroxisome localization	1	1872.4×	0.002	PEX16
microtubule-based peroxisome localization	1	936.2×	0.003	PEX1
peroxisome membrane biogenesis	1	624.1×	0.005	PEX16
protein import into peroxisome matrix, docking	1	468.1×	0.005	PEX5
response to amino acid starvation	1	468.1×	0.005	PEX2
endodermal cell fate commitment	1	312.1×	0.008	PAF1
mitochondrial membrane organization	1	267.5×	0.009	PEX5
cerebral cortex cell migration	1	170.2×	0.013	PEX5
cerebral cortex neuron differentiation	1	133.8×	0.016	PEX5
positive regulation of cell cycle G1/S phase transition	1	124.8×	0.016	PAF1
negative regulation of myeloid cell differentiation	1	104.0×	0.018	PAF1
cell development	1	98.5×	0.019	PEX5
protein tetramerization	1	69.3×	0.025	PEX5
mRNA 3’-end processing	1	62.4×	0.027	PAF1
neuromuscular process	1	58.5×	0.028	PEX5
positive regulation of multicellular organism growth	1	55.1×	0.028	PEX5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 8

Druggability breadth: 4 of 9 evidence-associated genes (44%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAF1	1	2
PEX1	0	0
PEX26	0	0
GATAD1	0	0
PEX16	0	0
PEX3	0	0
PEX6	0	0
PEX2	0	0
PEX5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	PAF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PAF1	8	Binding:8
PEX16	1	Binding:1
PEX3	1	Binding:1
PEX2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PEX1	3.6.4.7	peroxisome-assembly ATPase
PEX6	3.6.4.7	peroxisome-assembly ATPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	PAF1

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	1	PAF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	2	PEX1, PEX6
E	Difficult family or no structure, no drug	6	PEX26, GATAD1, PEX16, PEX3, PEX2, PEX5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PEX1	0	—
PEX26	0	—
GATAD1	0	—
PEX16	1	—
PEX3	1	—
PEX6	0	—
PEX2	1	—
PEX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.