PEX19 – Peroxisome Biogenesis Disorder

PEX19 is a peroxin essential for peroxisomal membrane synthesis and de novo formation of peroxisomes. Inherited in an autosomal recessive manner, homozygous loss-of-function variants in PEX19 impair peroxisome assembly and lead to peroxisome biogenesis disorders (PBD) (PMID:20683989).

A female infant born to first-degree cousins presented in the neonatal period with poor sucking, hypotonia, lethargy and subtle dysmorphic features. She developed seizures with EEG abnormalities, conjugated and unconjugated hyperbilirubinemia, elevated very-long-chain fatty acids, and defective plasmalogen biosynthesis and peroxisomal β-oxidation in fibroblasts, with complete absence of peroxisomes on immunofluorescence. Complementation grouped her PBD to PEX19, and mutation analysis revealed homozygosity for c.320del (p.Lys107SerfsTer13) ([PMID:20683989]). The patient’s clinical course included pneumonia, liver impairment, sepsis, epilepsy, gallstones, proteinuria and aminoaciduria reflecting a renal tubular defect.

Population screening in Poland identified 8 PBD patients among 1 264 suspected cases (frequency 0.20 per 100 000), with a strong correlation between serum C26:0 levels and survival (r2 = 0.822) ([PMID:20054782]). Eleven complementation groups for PBD have been mapped to distinct PEX genes, including PEX19, via functional complementation cloning and homology searches (PMID:11405337).

Functional studies of PEX19 splice isoforms showed that PEX19ΔE8 rescues peroxisome biogenesis in PEX19-deficient fibroblasts, whereas PEX19ΔE2 does not, indicating essential roles for specific domains in peroxisomal membrane assembly ([PMID:11883941]). Pentapeptide scanning mutagenesis delineated an N-terminal PEX3 docking domain, a central region competing for PEX14 binding, and a C-terminal domain interacting with multiple peroxisomal membrane proteins (PMPs) ([PMID:15713480]).

The PEX3–PEX19 complex has been crystallographically and functionally characterized: mutations in conserved PEX3 regions reduce PEX19 binding, destabilize PEX3, and block peroxisome biogenesis, highlighting a critical chaperone-receptor mechanism in early peroxisome formation ([PMID:22624858]). These data converge on a loss-of-function mechanism for PEX19 variants in PBD.

References

• American journal of medical genetics. Part A • 2010 • A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder. [PMID:20683989]
• Folia neuropathologica • 2009 • Serum very-long-chain fatty acids levels determined by gas chromatography in the diagnosis of peroxisomal disorders in Poland. [PMID:20054782]
• Journal of inherited metabolic disease • 2001 • Clinical, biochemical and genetic aspects and neuronal migration in peroxisome biogenesis disorders. [PMID:11405337]
• Biochemical and biophysical research communications • 2002 • Two splice variants of human PEX19 exhibit distinct functions in peroxisomal assembly. [PMID:11883941]
• Journal of molecular biology • 2005 • Analysis of human Pex19p's domain structure by pentapeptide scanning mutagenesis. [PMID:15713480]
• Traffic (Copenhagen, Denmark) • 2012 • The role of conserved PEX3 regions in PEX19-binding and peroxisome biogenesis. [PMID:22624858]

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