PEX6

Summary

PEX6 (peroxisomal biogenesis factor 6, HGNC:8859) is a protein-coding gene on chromosome 6p21.1, encoding Peroxisomal ATPase PEX6 (Q13608). 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. It is a selective cancer dependency (DepMap: 13.7% of cell lines).

This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5190 — RefSeq curated summary.

At a glance

• Gene–disease (curated): peroxisome biogenesis disorder (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 1,981 total — 112 pathogenic, 140 likely-pathogenic
• Phenotypes (HPO): 155
• Cancer dependency (DepMap): dependent in 13.7% of screened cell lines
• MANE Select transcript: NM_000287

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8859
Approved symbol	PEX6
Name	peroxisomal biogenesis factor 6
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	PXAAA1, PAF-2
Ensembl gene	ENSG00000124587
Ensembl biotype	protein_coding
OMIM	601498
Entrez	5190

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000244546, ENST00000304611, ENST00000858651, ENST00000858652, ENST00000858653, ENST00000858654, ENST00000858655, ENST00000858656, ENST00000858657, ENST00000858658, ENST00000970120, ENST00000970121, ENST00000970122, ENST00000970123

RefSeq mRNA: 2 — MANE Select: NM_000287 NM_000287, NM_001316313

CCDS: CCDS4877

Canonical transcript exons

ENST00000304611 — 17 exons

Exon	Start	End
ENSE00000850019	42966044	42966105
ENSE00000850020	42966242	42966447
ENSE00000850021	42966525	42966657
ENSE00000850022	42966782	42966858
ENSE00000850023	42967368	42967563
ENSE00000850024	42968290	42968498
ENSE00000850025	42968874	42968985
ENSE00000850026	42969668	42969801
ENSE00000850027	42969885	42969987
ENSE00000850028	42974003	42974086
ENSE00000850029	42974875	42975038
ENSE00001359565	42963865	42964471
ENSE00001716807	42978269	42979181
ENSE00003480128	42965075	42965152
ENSE00003606046	42964790	42964929
ENSE00003657511	42965681	42965789
ENSE00003688630	42965252	42965368

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 93.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.5080 / max 371.8702, expressed in 1793 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73648	13.3799	1783
73649	2.6725	1301
73650	0.4556	223

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	93.56	gold quality
body of pancreas	UBERON:0001150	93.51	gold quality
mucosa of transverse colon	UBERON:0004991	92.68	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.62	gold quality
right lobe of liver	UBERON:0001114	90.60	gold quality
cerebellar hemisphere	UBERON:0002245	89.75	gold quality
lower esophagus mucosa	UBERON:0035834	89.60	gold quality
adenohypophysis	UBERON:0002196	89.43	gold quality
right ovary	UBERON:0002118	89.40	gold quality
cerebellar cortex	UBERON:0002129	89.37	gold quality
left ovary	UBERON:0002119	88.89	gold quality
right frontal lobe	UBERON:0002810	88.18	gold quality
pituitary gland	UBERON:0000007	87.42	gold quality
right adrenal gland	UBERON:0001233	87.37	gold quality
right lobe of thyroid gland	UBERON:0001119	87.35	gold quality
stromal cell of endometrium	CL:0002255	87.34	gold quality
left adrenal gland cortex	UBERON:0035825	86.96	gold quality
pancreas	UBERON:0001264	86.91	gold quality
gastrocnemius	UBERON:0001388	86.85	gold quality
left adrenal gland	UBERON:0001234	86.57	gold quality
apex of heart	UBERON:0002098	86.55	gold quality
cortical plate	UBERON:0005343	86.55	gold quality
body of stomach	UBERON:0001161	86.47	gold quality
right adrenal gland cortex	UBERON:0035827	86.26	gold quality
cerebellum	UBERON:0002037	86.24	gold quality
left lobe of thyroid gland	UBERON:0001120	86.22	gold quality
endocervix	UBERON:0000458	86.17	gold quality
body of uterus	UBERON:0009853	85.83	gold quality
muscle of leg	UBERON:0001383	85.79	gold quality
left uterine tube	UBERON:0001303	85.16	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR

miRNA regulators (miRDB)

10 targeting PEX6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-4691-3P	98.11	66.83	1204

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 13.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 25)

• A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents (PMID:11873320)
• Insufficient binding to Pex1p x Pex6p complexes, or mislocalization of patient-derived Pex26p mutants is most likely responsible for the complementation group impaired peroxisome biogenesis. (PMID:16257970)
• the relative fraction of disease-causing alleles that occur in the coding and splice junction sequences of PEX6 gene. (PMID:19105186)
• Leigh syndrome presenting the T8993G mutation in the ATPase 6 gene with variable heteroplasmic loads (44-98%) in a single Tunisian family is a novel finding. (PMID:19433277)
• We identified a total of 77 different mutations in Zellweger syndrome patients of which 47 mutations have not been reported previously, and 14 polymorphic variants. (PMID:19877282)
• hybrid exercise increases expression of eukaryotic translation initiation factor 5A (EIFSA), peroxisomal biogenesis factor 6 (PEX6) and histone cluster 1 H4 (HIST1H4), compared with electrical stimulation alone (PMID:21778671)
• increased incidence of Zellweger syndrome in French-Canadians of Lac-St-Jean region caused by a PEX6 founder mutation (PMID:22894767)
• results suggested that peroxisome biogenesis requires Pex1p- and Pex6p-regulated dissociation of Pex14p from Pex26p (PMID:25016021)
• Mutations in PEX6 gene is associated with Heimler Syndrome. (PMID:26387595)
• Our structural data suggest that the tilting of a central segment of a Pex1-Pex6 pair is responsible for polypeptide movement. (PMID:26476099)
• PEX6 is expressed in photoreceptor cilia and mutated in deafblindness with enamel dysplasia and microcephaly. (PMID:26593283)
• PEX6 identified as the 6p21 SCABD gene in a family with spinocerebellar ataxia with blindness and deafness. (PMID:26669662)
• Heimler syndrome is due to four novel and two known missense variants and an 8 bp deletion in PEX6 in five families. (PMID:27302843)
• As standard biochemical screening of blood for evidence of a peroxisomal disorder did not provide a diagnosis in the individuals with Heimler syndrome, patients with sensorineural hearing lossand retinal pigmentation should have mutation analysis of PEX1 and PEX6 genes. (PMID:27633571)
• the current study revealed novel expression quantitative trait loci (eQTLs) for SNHG5 and PEX6 genes in chromosome 6. Nucleotide substitutions of the eQTLs might be candidate factors for a variety of cancers by regulating expression of the 2 genes. (PMID:28033303)
• A novel homozygous PEX6 p.Ala94Pro mutation. (PMID:29047053)
• Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. (PMID:29220678)
• Mutation in PAX6 gene is associated with Ophthalmic manifestations of Heimler syndrome. (PMID:29676688)
• This study provides evidence suggesting that monoubiquitinated PEX5 interacts directly with both PEX1 and PEX6 through its ubiquitin moiety and that the PEX5 polypeptide chain is globally unfolded during the ATP-dependent extraction event. (PMID:29884772)
• This article reviews the abundant records of missense mutations described in Peroxisome biogenesis disorders patients with the aim to classify and rationalize them by mapping them onto a homology model of the human Pex1/Pex6 complex. [review] (PMID:31374812)
• There are no significant differences between PEX1-, PEX6-, and PEX26-associated phenotypes inclinical and genetic spectrum of Heimler syndrome. (PMID:31831025)
• Exome sequencing identifies PEX6 mutations in three cases diagnosed with Retinitis Pigmentosa and hearing impairment. (PMID:32214787)
• The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature. (PMID:32866347)
• A homozygous Gly470Ala variant in PEX6 causes severe Zellweger spectrum disorder. (PMID:37144748)
• [Zellweger syndrome caused by PEX6 gene variation in 2 cases and literature review]. (PMID:38154976)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pex6	ENSDARG00000070958
mus_musculus	Pex6	ENSMUSG00000002763
rattus_norvegicus	Pex6	ENSRNOG00000016655
drosophila_melanogaster	Pex6	FBGN0033564
caenorhabditis_elegans		WBGENE00004195

Paralogs (5): PEX1 (ENSG00000127980), NVL (ENSG00000143748), AFG2A (ENSG00000145375), VCP (ENSG00000165280), AFG2B (ENSG00000171763)

Protein

Protein identifiers

Peroxisomal ATPase PEX6 — Q13608 (reviewed: Q13608)

Alternative names: Peroxin-6, Peroxisomal biogenesis factor 6, Peroxisomal-type ATPase 1, Peroxisome assembly factor 2

All UniProt accessions (1): Q13608

UniProt curated annotations — full annotation on UniProt →

Function. 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. Specifically recognizes PEX5 monoubiquitinated at ‘Cys-11’, and pulls it out of the peroxisome lumen through the PEX2-PEX10-PEX12 retrotranslocation channel. Extraction by the PEX1-PEX6 AAA ATPase complex is accompanied by unfolding of the TPR repeats and release of bound cargo from PEX5.

Subunit / interactions. Interacts with PEX1; forming the PEX1-PEX6 AAA ATPase complex, which is composed of a heterohexamer formed by a trimer of PEX1-PEX6 dimers. Interacts with PEX26; interaction is direct and promotes recruitment to peroxisomal membranes. Interacts with ZFAND6.

Subcellular location. Cytoplasm. Cytosol. Peroxisome membrane. Cell projection. Cilium. Photoreceptor outer segment.

Tissue specificity. Expressed in the retina, at higher levels in the photoreceptor layer at the joint between the outer and inner segments.

Disease relevance. Peroxisome biogenesis disorder complementation group 4 (PBD-CG4) [MIM:614862] A peroxisomal disorder arising from a failure of protein import into the peroxisomal membrane or matrix. The peroxisome biogenesis disorders (PBD group) are genetically heterogeneous with at least 14 distinct genetic groups as concluded from complementation studies. Include disorders are: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). ZWS, NALD and IRD are distinct from RCDP and constitute a clinical continuum of overlapping phenotypes known as the Zellweger spectrum (PBD-ZSS). The disease is caused by variants affecting the gene represented in this entry. Peroxisome biogenesis disorder 4A (PBD4A) [MIM:614862] A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and clinically characterized by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life. The disease is caused by variants affecting the gene represented in this entry. Peroxisome biogenesis disorder 4B (PBD4B) [MIM:614863] A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. The disease is caused by variants affecting the gene represented in this entry. Heimler syndrome 2 (HMLR2) [MIM:616617] A form of Heimler syndrome, a very mild peroxisome biogenesis disorder characterized by sensorineural hearing loss, amelogenesis imperfecta resulting in enamel hyoplasia of the secondary dentition, nail defects, and occasional or late-onset retinal pigmentation abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the AAA ATPase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q13608-1	1	yes
Q13608-2	2
Q13608-3	3

RefSeq proteins (2): NP_000278, NP_001303242 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR047533	RecA-like_PEX6_r2	Domain
IPR050168	AAA_ATPase_domain	Family
IPR057604	DPBB_PEX6	Domain
IPR057605	PEX6_N	Domain

Pfam: PF00004, PF25394, PF25395

Enzyme classification (BRENDA):

• EC 3.6.4.7 — peroxisome-assembly ATPase (BRENDA: 15 organisms, 53 substrates, 5 inhibitors, 2 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.17–0.7	2

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (32 total): sequence variant 20, mutagenesis site 4, splice variant 3, binding site 2, chain 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13608-F1	69.87	0.01

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (2): 470–477; 744–751

Post-translational modifications (1): 119

Mutagenesis-validated functional residues (4):

Position	Phenotype
476	in a1 mutant; abolished atp-binding; decreased interaction with pex1 or pex26.
532	in b1 mutant; abolished atp hydrolysis; does not affect interaction with pex6 or pex26.
750	in a2 mutant; abolished atp-binding; decreased interaction with pex1 or pex26.
803	in b2 mutant; does not affect interaction with pex6 or pex26.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9033241	Peroxisomal protein import

MSigDB gene sets: 430 (showing top): GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, GGAANCGGAANY_UNKNOWN, GOBP_PROTEIN_STABILIZATION, BROWNE_HCMV_INFECTION_14HR_DN, GOBP_RECEPTOR_METABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOBP_PEROXISOMAL_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GOCC_NEURON_PROJECTION

GO Biological Process (7): protein targeting to peroxisome (GO:0006625), peroxisome organization (GO:0007031), protein import into peroxisome matrix (GO:0016558), protein import into peroxisome matrix, translocation (GO:0016561), protein import into peroxisome matrix, receptor recycling (GO:0016562), protein unfolding (GO:0043335), protein stabilization (GO:0050821)

GO Molecular Function (8): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), protein-containing complex binding (GO:0044877), ubiquitin-modified protein reader activity (GO:0140036), protein transporter activity (GO:0140318), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): photoreceptor outer segment (GO:0001750), cytoplasm (GO:0005737), peroxisome (GO:0005777), peroxisomal membrane (GO:0005778), cytosol (GO:0005829), photoreceptor cell cilium (GO:0097733), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein localization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
establishment of protein localization to peroxisome	2
protein import into peroxisome matrix	2
binding	2
protein targeting	1
organelle organization	1
peroxisomal membrane transport	1
protein transmembrane import into intracellular organelle	1
protein localization to peroxisome	1
intracellular protein transmembrane transport	1
receptor recycling	1
cellular process	1
regulation of protein stability	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
ubiquitin-like protein reader activity	1
transporter activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
photoreceptor cell cilium	1
intracellular anatomical structure	1
microbody	1
peroxisome	1
microbody membrane	1
cytoplasm	1
neuron projection	1
9+0 non-motile cilium	1

Protein interactions and networks

STRING

2430 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PEX6	PEX26	Q7Z412	998
PEX6	PEX5	P50542	980
PEX6	PEX12	O00623	975
PEX6	PEX10	O60683	973
PEX6	PEX13	Q92968	973
PEX6	PEX7	O00628	970
PEX6	PEX3	P56589	968
PEX6	PEX2	P28328	962
PEX6	PEX16	Q9Y5Y5	959
PEX6	PEX19	P40855	957
PEX6	PEX14	O75381	931
PEX6	GABARAPL2	P60520	918
PEX6	PEX5L	Q8IYB4	908
PEX6	F5GZY7	F5GZY7	864
PEX6	ABITRAM	Q9NX38	864

IntAct

84 interactions, top by confidence:

A	B	Type	Score
PSMC3	PSMD9	psi-mi:“MI:0914”(association)	0.940
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMC3	PSMD12	psi-mi:“MI:0914”(association)	0.640
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
KBTBD4	KPNA5	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
LPCAT1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
PEX6	PEX1	psi-mi:“MI:0915”(physical association)	0.400
PEX1	PEX6	psi-mi:“MI:0915”(physical association)	0.400
RPL27A	PEX6	psi-mi:“MI:0915”(physical association)	0.370
PEX6	RPS14	psi-mi:“MI:0915”(physical association)	0.370
PEX6	CERS2	psi-mi:“MI:0915”(physical association)	0.370
ATF7IP	PEX6	psi-mi:“MI:0915”(physical association)	0.370
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
OLFM2	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
PSMC3		psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
ENSA	QSOX1	psi-mi:“MI:0914”(association)	0.350
	DENND11	psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CTLA4	TMEM120B	psi-mi:“MI:0914”(association)	0.350
OSTM1	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (106): PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-MS), PEX6 (Affinity Capture-Western), PEX6 (Reconstituted Complex)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

Diamond homologs: A0A061IR73, A0A7N9VSG0, A4G0S4, A6UQT3, A6VHR1, A7YSY2, A9A916, C4QXI8, C4R6C2, D1CDT8, D4A2B7, G1X4S3, G1X7C7, G3GXG9, O05209, O13764, O14325, O15381, O18413, O26824, O28303, O28972, O43933, O60058, O74941, P03974, P23787, P24004, P25694, P32794, P33289, P33760, P34124, P36966, P41836, P46462, P46463, P46468, P54609, P54774

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
PEX6	up-regulates	Protein_localization_to_peroxisome
PEX26	“up-regulates activity”	PEX6	binding
PEX6	“up-regulates activity”	PEX1	binding
PEX6	“up-regulates activity”	PEX5	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1981 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	112
Likely pathogenic	140
Uncertain significance	642
Likely benign	874
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1013290	NM_000287.4(PEX6):c.1090C>T (p.Gln364Ter)	Pathogenic
1019386	NM_000287.4(PEX6):c.2585G>T (p.Gly862Val)	Pathogenic
1071131	NM_000287.4(PEX6):c.1216dup (p.His406fs)	Pathogenic
1072637	NM_000287.4(PEX6):c.1798C>T (p.Gln600Ter)	Pathogenic
1073363	NM_000287.4(PEX6):c.1357del (p.Leu453fs)	Pathogenic
1073678	NM_000287.4(PEX6):c.1681del (p.Leu561fs)	Pathogenic
1075322	NM_000287.4(PEX6):c.706C>T (p.Gln236Ter)	Pathogenic
1075830	NM_000287.4(PEX6):c.1805del (p.Leu602fs)	Pathogenic
1323439	NM_000287.4(PEX6):c.1313dup (p.Glu439fs)	Pathogenic
1356953	NM_000287.4(PEX6):c.2470del (p.Arg824fs)	Pathogenic
1357208	NM_000287.4(PEX6):c.2754_2758del (p.Cys918_Asp920delinsTer)	Pathogenic
1380352	NM_000287.4(PEX6):c.2T>C (p.Met1Thr)	Pathogenic
1384356	NM_000287.4(PEX6):c.1782_1807dup (p.Ser603fs)	Pathogenic
1418343	NM_000287.4(PEX6):c.738_741del (p.Glu246fs)	Pathogenic
1424285	NM_000287.4(PEX6):c.1156A>T (p.Lys386Ter)	Pathogenic
1438556	NM_000287.4(PEX6):c.212del (p.Pro71fs)	Pathogenic
1451508	NC_000006.12:g.42965156_42965157insTTTTTTTTTTTTTTTTTNNNNNNNNNNAGACGGGGTTTCACCGTTTTAGCCGGGATGGTCTCGATCTCCTGACCTCGTGATCCGCCCGCCTCGGCCTCCCAAAGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCACAGCTTGTCAAATCTTT	Pathogenic
1451673	NM_000287.4(PEX6):c.856del (p.Leu286fs)	Pathogenic
1451674	NM_000287.4(PEX6):c.814_817dup (p.Val273fs)	Pathogenic
1451675	NM_000287.4(PEX6):c.689_690del (p.Glu230fs)	Pathogenic
1452645	NM_000287.4(PEX6):c.1690_1693dup (p.Pro565fs)	Pathogenic
1452760	NM_000287.4(PEX6):c.514dup (p.Asp172fs)	Pathogenic
1454612	NM_000287.4(PEX6):c.1109_1112del (p.Gly370fs)	Pathogenic
1454841	NC_000006.11:g.(?42941721)(42942796_?)del	Pathogenic
1456026	NM_000287.4(PEX6):c.1138dup (p.Glu380fs)	Pathogenic
1456403	NM_000287.4(PEX6):c.630del (p.Cys211fs)	Pathogenic
1458568	NM_000287.4(PEX6):c.2205del (p.Arg736fs)	Pathogenic
1459247	NM_000287.4(PEX6):c.1404del (p.Arg469fs)	Pathogenic
1804023	NM_000287.4(PEX6):c.2665A>G (p.Lys889Glu)	Pathogenic
194165	NM_000287.4(PEX6):c.2440C>T (p.Arg814Ter)	Pathogenic

SpliceAI

3248 predictions. Top by Δscore:

Variant	Effect	Δscore
6:42960972:GG:G	donor_gain	1.0000
6:42960973:GG:G	donor_gain	1.0000
6:42962196:C:CA	acceptor_gain	1.0000
6:42962199:T:TA	acceptor_gain	1.0000
6:42962200:G:A	acceptor_gain	1.0000
6:42962203:C:CA	acceptor_gain	1.0000
6:42962210:A:AG	acceptor_gain	1.0000
6:42962210:AG:A	acceptor_gain	1.0000
6:42962210:AGGGT:A	acceptor_gain	1.0000
6:42962211:G:GT	acceptor_gain	1.0000
6:42962211:GG:G	acceptor_gain	1.0000
6:42962211:GGGTG:G	acceptor_gain	1.0000
6:42962335:GTGGG:G	donor_gain	1.0000
6:42962337:GGG:G	donor_gain	1.0000
6:42962338:GGG:G	donor_gain	1.0000
6:42962338:GGGTA:G	donor_loss	1.0000
6:42962340:G:GC	donor_loss	1.0000
6:42962341:T:G	donor_loss	1.0000
6:42962752:T:A	acceptor_gain	1.0000
6:42962758:CTAGT:C	acceptor_loss	1.0000
6:42962759:TA:T	acceptor_loss	1.0000
6:42962760:A:AG	acceptor_gain	1.0000
6:42962760:A:G	acceptor_loss	1.0000
6:42962761:G:GA	acceptor_gain	1.0000
6:42962761:GT:G	acceptor_gain	1.0000
6:42962761:GTC:G	acceptor_gain	1.0000
6:42962761:GTCA:G	acceptor_gain	1.0000
6:42962761:GTCAT:G	acceptor_gain	1.0000
6:42962876:AAG:A	donor_gain	1.0000
6:42962877:AG:A	donor_gain	1.0000

AlphaMissense

6165 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:42965354:A:G	L829P	0.999
6:42965744:T:A	D803V	0.998
6:42966063:A:C	S781R	0.998
6:42966063:A:T	S781R	0.998
6:42966065:T:G	S781R	0.998
6:42966088:A:G	L773P	0.998
6:42966247:G:C	F765L	0.998
6:42966247:G:T	F765L	0.998
6:42966249:A:G	F765L	0.998
6:42966269:G:T	A758D	0.998
6:42966281:G:T	A754D	0.998
6:42965267:A:T	L858H	0.997
6:42965293:G:C	N849K	0.997
6:42965293:G:T	N849K	0.997
6:42965303:C:T	G846E	0.997
6:42965726:G:T	A809D	0.997
6:42965741:T:A	E804V	0.997
6:42965741:T:G	E804A	0.997
6:42965742:C:T	E804K	0.997
6:42966276:C:G	A756P	0.997
6:42966296:C:T	G749D	0.997
6:42965252:C:G	R863T	0.996
6:42965297:G:A	T848I	0.996
6:42965738:A:G	L805P	0.996
6:42965744:T:G	D803A	0.996
6:42965785:A:C	F789L	0.996
6:42965785:A:T	F789L	0.996
6:42965787:A:G	F789L	0.996
6:42966302:C:T	G747D	0.996
6:42966311:C:T	G744E	0.996

dbSNP variants (sampled 300 via entrez): RS1000377979 (6:42968211 A>G), RS1000707681 (6:42969349 T>C), RS1000940698 (6:42964546 C>G), RS1001052245 (6:42964324 C>G,T), RS1001291566 (6:42971701 C>T), RS1001345963 (6:42977970 A>G), RS1002456656 (6:42979227 G>A,C), RS1002648497 (6:42981178 CAAAAAAATAAATAATAG>C), RS1002946677 (6:42969763 T>G), RS1002960981 (6:42969141 C>T), RS1003036234 (6:42972751 C>A,T), RS1003122928 (6:42976262 C>G,T), RS1003315405 (6:42970993 G>A), RS1003388274 (6:42969454 C>G), RS1003457022 (6:42978006 G>A)

Disease associations

OMIM: gene MIM:601498 | disease phenotypes: MIM:214100, MIM:271250, MIM:614863, MIM:614862, MIM:312080, MIM:202370

GenCC curated gene-disease

Disease	Classification	Inheritance
peroxisome biogenesis disorder	Definitive	Autosomal recessive
peroxisome biogenesis disorder 4A (Zellweger)	Definitive	Autosomal recessive
peroxisome biogenesis disorder 4B	Definitive	Autosomal recessive
Heimler syndrome 2	Moderate	Autosomal recessive
Zellweger spectrum disorders	Supportive	Autosomal recessive
autosomal recessive cerebellar ataxia-blindness-deafness syndrome	Supportive	Autosomal recessive
Perrault syndrome	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
peroxisome biogenesis disorder	Definitive	AR

Mondo (17): peroxisome biogenesis disorder (MONDO:0019234), Zellweger spectrum disorders (MONDO:0019609), peroxisome biogenesis disorder 4B (MONDO:0013931), peroxisome biogenesis disorder 4A (Zellweger) (MONDO:0013930), megalencephaly (MONDO:0016608), leukodystrophy (MONDO:0019046), inherited retinal dystrophy (MONDO:0019118), peroxisome biogenesis disorder 2B (MONDO:0008736), cerebellar ataxia (MONDO:0000437), premature menopause (MONDO:0001119), peripheral neuropathy (MONDO:0005244), paroxysmal dystonia (MONDO:0016058), sensorineural hearing loss disorder (MONDO:0020678), peroxisome biogenesis disorder 1A (Zellweger) (MONDO:0008953), (MONDO:0010061)

Orphanet (11): Peroxisome biogenesis disorder (Orphanet:79189), Zellweger syndrome (Orphanet:912), Deafness-enamel hypoplasia-nail defects syndrome (Orphanet:3220), Neonatal adrenoleukodystrophy (Orphanet:44), Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome (Orphanet:95433), Leukodystrophy (Orphanet:68356), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare ataxia (Orphanet:102002), Paroxysmal dystonia (Orphanet:200037), Infantile Refsum disease (Orphanet:772), Isolated megalencephaly (Orphanet:2477)

HPO phenotypes

155 total (30 of 155 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000070	Ureterocele
HP:0000107	Renal cyst
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000157	Abnormality of the tongue
HP:0000164	Abnormality of the dentition
HP:0000174	Abnormal palate morphology
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000260	Wide anterior fontanel
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000286	Epicanthus
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000377	Abnormal pinna morphology
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000474	Thickened nuchal skin fold

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002813_5	Alzheimer’s disease in APOE e4+ carriers	7.000000e-06
GCST90002383_414	Hematocrit	1.000000e-09
GCST90002403_154	Red blood cell count	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004348	hematocrit
EFO:0004305	erythrocyte count

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D058627	Megalencephaly	C05.660.207.536; C10.500.507.400.249; C16.131.621.207.532; C16.131.666.507.400.249
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D058499	Retinal Dystrophies	C11.768.585.658
D015211	Zellweger Syndrome	C06.552.970; C10.228.140.163.100.968; C12.050.351.968.419.978; C12.200.777.419.978; C12.950.419.978; C16.131.077.970; C16.320.565.189.968; C16.320.565.663.970; C18.452.132.100.968; C18.452.648.189.968; C18.452.648.663.970
C563301	Peroxisome Biogenesis Disorder, Complementation Group 4 (supp.)
C536664	Peroxisome biogenesis disorders (supp.)
C537309	Spinocerebellar ataxia, autosomal recessive 10 (supp.)
C531857	Zellweger leukodystrophy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
Temozolomide	increases expression	1
Lead	affects expression	1
Nickel	decreases expression	1
Quercetin	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

299 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT01838941	PHASE3	COMPLETED	Betaine and Peroxisome Biogenesis Disorders
NCT00007020	PHASE3	COMPLETED	Compassionate Treatment of Patients With Inborn Errors of Bile Acid Metabolism With Cholic Acid
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT03856866	PHASE2	COMPLETED	Hydroxychloroquine Administration for Reduction of Pexophagy
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis