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PEX16
peroxisomal biogenesis factor 16
PEX16 is located on the short (p) arm of chromosome 11, at band 11p11.2. Arm ratio per GRCh38 - banding schematic.
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Overview
PEX16 (peroxisomal biogenesis factor 16) is located on chromosome 11p11.2 and encodes a 336-amino acid membrane protein critical for peroxisome assembly. Peroxisomes are small organelles responsible for breaking down very long-chain fatty acids, synthesising plasmalogens (specialised lipids found in myelin and cell membranes), and detoxifying reactive oxygen species. The PEX16 protein is among the first peroxins to arrive at the endoplasmic reticulum membrane, where it initiates the formation of nascent peroxisome structures. Without functional PEX16, cells cannot generate peroxisomes, resulting in accumulation of toxic metabolic intermediates and deficiency of essential lipids. Conditions caused by PEX16 variants follow an autosomal recessive inheritance pattern, meaning two pathogenic copies are required for disease to manifest.
What the gene does
The PEX16 protein serves as a membrane anchor and recruitment platform during the earliest stages of peroxisome biogenesis. It embeds itself in the endoplasmic reticulum membrane and acts as a docking site for PEX3 and PEX19, two other peroxisomal proteins that coordinate the import of additional membrane and matrix proteins. This sequential recruitment process establishes the foundational structure from which mature peroxisomes emerge. Research suggests that PEX16 facilitates the budding of pre-peroxisomal vesicles from the endoplasmic reticulum, which then mature into functional organelles capable of metabolic activity. The protein's role is particularly critical in tissues with high metabolic demand, such as the liver and brain, where peroxisomes perform essential fatty acid oxidation and lipid synthesis. Loss of PEX16 function prevents the entire peroxisome assembly pathway from initiating, leading to cellular accumulation of very long-chain fatty acids and deficiency of plasmalogens, both of which are toxic to developing neural tissue.
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Chromosome location
PEX16 is located on the short arm of chromosome 11 at band p11.2. This chromosomal region contains multiple genes involved in metabolic and developmental processes. The gene comprises several exons that encode the 336-amino acid protein, though the precise exon-intron structure varies slightly across reported isoforms. The 11p11.2 region is not associated with common chromosomal rearrangements, and most pathogenic changes in PEX16 arise from single-nucleotide variants or small insertions and deletions rather than large structural alterations.
Protein structure
The PEX16 protein contains several functionally important regions distributed across its 336-amino acid sequence. The segment spanning amino acids 66-81 is required for peroxisomal location, ensuring the protein correctly targets to the endoplasmic reticulum membrane where peroxisome formation begins. Two disordered regions (amino acids 142-171 and 184-210) likely provide structural flexibility that facilitates protein-protein interactions during the dynamic assembly process. The C-terminal region from amino acids 221-336 mediates interaction with PEX19, a chaperone protein that delivers newly synthesised peroxisomal membrane proteins to the growing organelle. This interaction domain is essential for PEX16's function as a recruitment platform, and variants disrupting this region can abolish peroxisome biogenesis even if the rest of the protein remains intact.
Key variants
Pathogenic variants in PEX16 are uncommon but result in severe peroxisomal biogenesis disorders when present in both gene copies. Reported variants include missense changes that disrupt protein folding or interaction surfaces, nonsense mutations that truncate the protein prematurely, and small frameshift deletions. The majority of disease-causing variants cluster in regions critical for PEX19 interaction or membrane anchoring. Carrier status (one pathogenic variant) does not cause symptoms, as a single functional copy of PEX16 is sufficient for normal peroxisome assembly. Due to the rarity of these variants, population carrier frequencies are low, though certain founder mutations have been identified in specific populations.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.526C>T | p.Arg176Ter | Pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.859C>T | p.Arg287Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder 8A (Zellweger) |
c.860G>A | p.Arg287His | Pathogenic/Likely pathogenic | ★★☆☆ | Peroxisome biogenesis disorder |
c.140dup | p.Glu48fs | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.146del | p.Leu49fs | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.238C>T | p.Gln80Ter | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.254G>A | p.Trp85Ter | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.512C>A | p.Ser171Ter | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.51_52del | p.His18fs | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
c.714G>A | p.Trp238Ter | Pathogenic | ★☆☆☆ | Peroxisome biogenesis disorder |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in PEX16 cause peroxisomal biogenesis disorders, a spectrum of severe conditions characterised by absent or severely reduced peroxisome function. The most severe presentation, Zellweger syndrome, manifests in infancy with distinctive craniofacial features, profound hypotonia, liver dysfunction, and seizures, typically leading to early mortality. Milder phenotypes in the Zellweger spectrum may present in childhood with developmental delay, vision loss due to retinal degeneration, hearing impairment, and progressive white matter abnormalities. The severity of disease generally correlates with the degree of residual PEX16 function, though genotype-phenotype predictions remain challenging given the rarity of reported cases. All affected individuals show biochemical hallmarks including elevated very long-chain fatty acids and reduced plasmalogen levels.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PEX16 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
PEX16 appears on multiple NHS Genomic Medicine Service panels with green classification, indicating strong evidence for its role in disease. The gene is included on panels for peroxisomal disorders, likely inborn errors of metabolism, and undiagnosed metabolic disorders, reflecting its central role in peroxisome biogenesis. It also features on panels for inherited white matter disorders, intellectual disability, and neonatal cholestasis, consistent with the multisystem manifestations of peroxisomal dysfunction. Additional panel memberships include ataxia and cerebellar anomalies, bilateral congenital cataracts, and foetal anomalies, highlighting the prenatal and neurological features often seen in affected individuals. The gene's presence on the DDG2P (Developmental Disorders Genotype-to-Phenotype) panel underscores its relevance to neurodevelopmental presentations.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does it mean to be a carrier of a PEX16 variant?
A carrier has one pathogenic variant in PEX16 and one normal copy. Carriers do not develop peroxisomal disorders because the single functional copy produces sufficient protein for normal peroxisome assembly. Carrier status is clinically silent but may be relevant for family planning if a partner is also a carrier.
How are peroxisomal biogenesis disorders diagnosed?
Diagnosis typically begins with biochemical testing showing elevated very long-chain fatty acids and reduced plasmalogens in blood or fibroblasts. Genetic testing of PEX16 and other peroxisomal genes confirms the diagnosis and identifies the specific variants. Imaging may reveal characteristic brain abnormalities.
Is PEX16 testing available through the NHS?
Yes, PEX16 is included in multiple NHS Genomic Medicine Service gene panels. Testing is typically arranged by clinical genetics services or metabolic specialists when clinical and biochemical findings suggest a peroxisomal disorder.