peroxisome biogenesis disorder 4A (Zellweger)

Summary

peroxisome biogenesis disorder 4A (Zellweger) (MONDO:0013930) is a disease caused by PEX6 (GenCC Definitive), with 4 cohort genes. The dominant Reactome pathway is Peroxisomal protein import (3 cohort genes).

At a glance

• Causal gene: PEX6 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 221

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	peroxisome biogenesis disorder 4A (Zellweger)
Mondo ID	MONDO:0013930
MeSH	C563301
OMIM	614862
DOID	DOID:0080479
NCIT	C155754
UMLS	C3553936
MedGen	766850
GARD	0015859
Is cancer (heuristic)	no

Also known as: classic peroxisome biogenesis disorder · PBD4A · peroxisome biogenesis disorder 4A (Zellweger)

Data availability: 221 ClinVar variants · 3 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 PEX6 defect › peroxisome biogenesis disorder 4A (Zellweger)

Related subtypes (1): peroxisome biogenesis disorder 4B

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

221 retrieved; paginated sample, class counts are floors:

61 likely pathogenic, 46 uncertain significance, 40 conflicting classifications of pathogenicity, 30 pathogenic/likely pathogenic, 18 pathogenic, 14 benign/likely benign, 9 benign, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
4278224	NM_004565.3(PEX14):c.488-1G>A	LOC126805616	Pathogenic	criteria provided, single submitter
4795152	NM_002618.4(PEX13):c.296del (p.Gly99fs)	PEX13	Pathogenic	criteria provided, single submitter
1069504	NM_000287.4(PEX6):c.727C>T (p.Gln243Ter)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071121	NM_000287.4(PEX6):c.1691del (p.Cys564fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323439	NM_000287.4(PEX6):c.1313dup (p.Glu439fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
1324885	NM_000287.4(PEX6):c.1326dup (p.Ser443fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356707	NM_000287.4(PEX6):c.531del (p.Pro179fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369876	NM_000287.4(PEX6):c.1415del (p.Pro472fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386889	NM_000287.4(PEX6):c.2722C>T (p.Gln908Ter)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447140	NM_000287.4(PEX6):c.914_923del (p.Asp305fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1515421	NM_000287.4(PEX6):c.2734G>A (p.Ala912Thr)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804023	NM_000287.4(PEX6):c.2665A>G (p.Lys889Glu)	PEX6	Pathogenic	criteria provided, single submitter
194165	NM_000287.4(PEX6):c.2440C>T (p.Arg814Ter)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
2136394	NM_000287.4(PEX6):c.402del (p.Gly135fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
217424	NM_000287.4(PEX6):c.821C>T (p.Pro274Leu)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217426	NM_000287.4(PEX6):c.1841del (p.Leu614fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
224321	NM_000287.4(PEX6):c.1314_1321del (p.Glu439fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts
224323	NM_000287.4(PEX6):c.1715C>T (p.Thr572Ile)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2837695	NM_000287.4(PEX6):c.1A>T (p.Met1Leu)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593619	NM_000287.4(PEX6):c.2T>A (p.Met1Lys)	PEX6	Pathogenic	criteria provided, single submitter
446026	NM_000287.4(PEX6):c.1287del (p.Trp430fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
492968	NM_000287.4(PEX6):c.2578C>T (p.Arg860Trp)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
495796	NM_000287.4(PEX6):c.1947del (p.Ile650fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
499109	NM_000287.4(PEX6):c.311del (p.Gly104fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
550358	NM_000287.4(PEX6):c.1962-1G>A	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551023	NM_000287.4(PEX6):c.510dup (p.Gly171fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553235	NM_000287.4(PEX6):c.2082del (p.Gly695fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554303	NM_000287.4(PEX6):c.506_507del (p.Glu169fs)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555170	NM_000287.4(PEX6):c.2435G>A (p.Arg812Gln)	PEX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555443	NM_000287.4(PEX6):c.802_815del (p.Asp268fs)	PEX6	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 17 · 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
PEX6	Definitive	Autosomal recessive	peroxisome biogenesis disorder	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CFI	Orphanet:200418	Immunodeficiency with factor I anomaly
CFI	Orphanet:244242	HELLP syndrome
CFI	Orphanet:244275	De novo thrombotic microangiopathy after kidney transplantation
CFI	Orphanet:544472	Atypical hemolytic uremic syndrome with complement gene abnormality
CFI	Orphanet:75376	Familial drusen
PEX13	Orphanet:44	Neonatal adrenoleukodystrophy
PEX13	Orphanet:772	Infantile Refsum disease
PEX13	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

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	gencc,clinvar
CFI	HGNC:5394	ENSG00000205403	P05156	Complement factor I	clinvar
PEX13	HGNC:8855	ENSG00000162928	Q92968	Peroxisomal membrane protein PEX13	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)
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.
CFI	Complement factor I	Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.
PEX13	Peroxisomal membrane protein PEX13	Component of the PEX13-PEX14 docking complex, a translocon channel that specifically mediates the import of peroxisomal cargo proteins bound to PEX5 receptor.
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: 1 · 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
Protease	1	9.2×	0.392
Scaffold/PPI	1	4.3×	0.392
Enzyme (other)	1	3.0×	0.392
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
CFI	Protease	yes	3.4.21.45	SRCR, Trypsin_dom, Peptidase_S1A
PEX13	Scaffold/PPI	no		SH3_domain, Peroxin-13_N, Pex13
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
mucosa of transverse colon	1
right uterine tube	1
germinal epithelium of ovary	1
parietal pleura	1
right lobe of liver	1
oocyte	1
secondary oocyte	1
sperm	1
gastrocnemius	1
left testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon
CFI	240	broad	marker	germinal epithelium of ovary, parietal pleura, right lobe of liver
PEX13	264	ubiquitous	marker	secondary oocyte, sperm, oocyte
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PEX6	2,620
PEX5	1,741
PEX13	1,127
CFI	1,120

Intra-cohort edges

A	B	Sources
PEX13	PEX5	biogrid_interaction, string_interaction
PEX13	PEX6	string_interaction
PEX5	PEX6	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PEX5	P50542	11
PEX13	Q92968	3
CFI	P05156	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX6	Q13608	69.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 4 evidence-associated genes (4 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 4 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	3	129.8×	4e-06	PEX6, PEX13, PEX5
E3 ubiquitin ligases ubiquitinate target proteins	2	96.8×	4e-04	PEX13, PEX5
Pexophagy	1	237.9×	0.007	PEX5
Class I peroxisomal membrane protein import	1	129.8×	0.010	PEX13
Regulation of Complement cascade	1	58.3×	0.017	CFI

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 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, translocation	3	3159.8×	6e-10	PEX6, PEX13, PEX5
protein import into peroxisome matrix, docking	2	2106.5×	4e-06	PEX13, PEX5
protein import into peroxisome matrix, receptor recycling	2	1203.7×	9e-06	PEX6, PEX5
protein targeting to peroxisome	2	842.6×	1e-05	PEX6, PEX5
cerebral cortex cell migration	2	766.0×	1e-05	PEX13, PEX5
protein import into peroxisome matrix	2	702.2×	1e-05	PEX6, PEX5
cellular response to reactive oxygen species	2	205.5×	2e-04	PEX13, PEX5
neuron migration	2	66.9×	0.001	PEX13, PEX5
microtubule-based peroxisome localization	1	2106.5×	0.002	PEX13
protein unfolding	1	842.6×	0.003	PEX6
protein import into peroxisome matrix, substrate release	1	842.6×	0.003	PEX5
protein import into peroxisome membrane	1	702.2×	0.004	PEX5
fatty acid alpha-oxidation	1	601.9×	0.004	PEX13
mitochondrial membrane organization	1	601.9×	0.004	PEX5
suckling behavior	1	421.3×	0.005	PEX13
cerebral cortex neuron differentiation	1	300.9×	0.006	PEX5
pexophagy	1	263.3×	0.007	PEX5
cell development	1	221.7×	0.008	PEX5
peroxisome organization	1	200.6×	0.008	PEX6
very long-chain fatty acid metabolic process	1	191.5×	0.008	PEX5
protein tetramerization	1	156.0×	0.009	PEX5
complement activation, classical pathway	1	135.9×	0.010	CFI
neuromuscular process	1	131.7×	0.010	PEX5
positive regulation of multicellular organism growth	1	123.9×	0.010	PEX5
negative regulation of protein-containing complex assembly	1	113.9×	0.011	PEX5
endoplasmic reticulum organization	1	105.3×	0.011	PEX5
fatty acid beta-oxidation	1	93.6×	0.012	PEX5
locomotory behavior	1	44.8×	0.024	PEX13
protein stabilization	1	16.7×	0.063	PEX6
proteolysis	1	8.6×	0.114	CFI

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PEX6	0	0
CFI	0	0
PEX13	0	0
PEX5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PEX6	3.6.4.7	peroxisome-assembly ATPase
CFI	3.4.21.45	complement factor I

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	CFI
D	Druggable family + AlphaFold only, no drug	1	PEX6
E	Difficult family or no structure, no drug	2	PEX13, PEX5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PEX6	0	—
CFI	0	—
PEX13	0	—
PEX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.