PEX10 — Peroxisomal biogenesis factor 10

The PEX10 gene provides instructions for making a protein that is essential for the formation and function of peroxisomes. Peroxisomes are small, sac-like structures inside cells that act as recycling centers. They break down certain types of fats and toxic substances, and they help build important molecules needed for the brain and nervous system to work properly. The PEX10 protein acts like a gatekeeper, helping to bring necessary enzymes into the peroxisomes so they can do their job. When there is a mutation in the PEX10 gene, the peroxisomes cannot form correctly or do not work properly. This means that toxic substances and certain fats build up in the body's cells, while essential molecules are not produced in sufficient amounts. This buildup and deficiency cause severe damage to the brain, liver, kidneys, and eyes. Depending on the severity of the mutation, the effects on health can vary. Severe mutations cause Zellweger syndrome, which leads to profound developmental delays, weak muscle tone, seizures, vision and hearing loss, and liver problems, often resulting in death in infancy. Milder mutations can cause conditions like neonatal adrenoleukodystrophy or ataxia, where patients may have learning difficulties, balance problems, and progressive vision and hearing loss, but can survive into childhood or adulthood.

Gene description: The PEX10 gene encodes a peroxisomal membrane protein essential for peroxisome biogenesis and the import of peroxisomal matrix proteins. Mutations in this gene lead to Zellweger spectrum disorders, a group of severe, often fatal, genetic diseases characterized by neurological, hepatic, and renal abnormalities.

Patient and family guide: The PEX10 gene provides instructions for making a protein that is essential for the formation and function of peroxisomes. Peroxisomes are small, sac-like structures inside cells that act as recycling centers. They break down certain types of fats and toxic substances, and they help build important molecules needed for the brain and nervous system to work properly. The PEX10 protein acts like a gatekeeper, helping to bring necessary enzymes into the peroxisomes so they can do their job. When there is a mutation in the PEX10 gene, the peroxisomes cannot form correctly or do not work properly. This means that toxic substances and certain fats build up in the body's cells, while essential molecules are not produced in sufficient amounts. This buildup and deficiency cause severe damage to the brain, liver, kidneys, and eyes. Depending on the severity of the mutation, the effects on health can vary. Severe mutations cause Zellweger syndrome, which leads to profound developmental delays, weak muscle tone, seizures, vision and hearing loss, and liver problems, often resulting in death in infancy. Milder mutations can cause conditions like neonatal adrenoleukodystrophy or ataxia, where patients may have learning difficulties, balance problems, and progressive vision and hearing loss, but can survive into childhood or adulthood.

Gene function: The PEX10 protein is a peroxisomal membrane protein that functions as an E3 ubiquitin-protein ligase. It is a crucial component of the retrotranslocation channel required for peroxisome organization, mediating the export of the PEX5 receptor from the peroxisome to the cytosol. This process is essential for the continuous import of peroxisomal matrix proteins.

Protein structure: The PEX10 protein consists of 326 amino acids and contains two putative transmembrane segments. It features a highly conserved C3HC4 zinc finger RING motif at its C-terminus. Both the N-terminal and C-terminal regions of the protein are exposed to the cytosol, while the transmembrane domains anchor it to the peroxisomal membrane.

Molecular function: PEX10 functions as an E3 ubiquitin-protein ligase that is integral to the peroxisomal protein import machinery. It localizes to the peroxisomal membrane with its N- and C-terminal regions exposed to the cytosol. The protein contains a C3HC4 zinc finger RING motif at its C-terminus, which is critical for its ubiquitin ligase activity. PEX10 interacts with other peroxins, such as PEX2 and PEX12, to form a RING finger complex that ubiquitinates the cycling import receptor PEX5. This ubiquitination is required for the recycling of PEX5 back to the cytosol, a necessary step for the continuous import of newly synthesized matrix proteins into the peroxisome.

Mutation spectrum: The mutation spectrum of PEX10 includes nonsense, frameshift, splice site, and missense mutations. Severe loss-of-function mutations, such as large deletions or frameshifts (e.g., 2-bp deletion 814-815delCT, R125X), typically cause the severe Zellweger syndrome phenotype. Missense mutations (e.g., H290Q, L297P) that retain some residual function are often associated with milder phenotypes like neonatal adrenoleukodystrophy or childhood-onset ataxia.

Clinical significance: Mutations in the PEX10 gene cause peroxisome biogenesis disorders (PBDs) in the Zellweger spectrum, including Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. These mutations lead to impaired import of peroxisomal matrix proteins, resulting in the absence of functional peroxisomes or partial loss of peroxisomal function. This causes an accumulation of very long-chain fatty acids (VLCFAs), phytanic acid, and pristanic acid, and a deficiency in plasmalogens. Clinically, this manifests as severe neurological deficits, hypotonia, seizures, liver dysfunction, retinal degeneration, sensorineural deafness, and developmental delay. Milder mutations can cause childhood-onset cerebellar ataxia and neuropathy.

Inheritance: Autosomal Recessive

Chromosomal location: 1p36.32

Research and therapeutic approaches: Currently, there is no curative treatment for PEX10-related Zellweger spectrum disorders, and management is primarily supportive and symptom-based. However, experimental approaches are being explored. Gene therapy using viral vectors to deliver a functional copy of the PEX10 gene has shown potential in preclinical studies to improve retinal and neurological functions. Additionally, research into base editing techniques aims to correct specific genetic mutations at the DNA level, offering hope for future targeted therapies.