PEX19 – Zellweger spectrum disorders

PEX19 encodes a peroxin essential for peroxisomal membrane protein targeting, and biallelic mutations cause Zellweger spectrum disorders. A neonate presented with hypertelorism, depressed nasal bridge, ventricular septal defect, webbed neck, simian crease, cryptorchidism, hypospadias, talipes equinovarus, hypotonia, micrognathia and cerebellar vermis hypoplasia; clinical exome sequencing identified a rare homozygous PEX19 variant, and a similarly affected sibling supports autosomal recessive inheritance (PMID:36931687).

Several functional studies elucidate PEX19’s domain architecture and mechanism of action. Splice variant PEX19DeltaE8 restores peroxisome biogenesis in PEX19-deficient fibroblasts whereas PEX19DeltaE2 does not (PMID:11883941). Pentapeptide-scanning mutagenesis defined N-terminal, central and C-terminal regions required for PEX3 interaction and peroxisomal membrane protein assembly (PMID:15713480). Structural studies of PEX14 reveal competitive binding of PEX19 at a conserved F/YFxxxF motif (PMID:19197237), and site-directed mutagenesis of PEX3-binding sites in PEX3 confirms PEX19’s role in de novo peroxisome formation (PMID:22624858). An inducible isoform PEX19i highlights the essential C-terminal domain in early peroxisome proliferation (PMID:28391327). These data support a loss-of-function mechanism underpinning Zellweger spectrum disorders. Key take-home: AR PEX19 variants disrupt peroxisomal biogenesis, guiding molecular diagnosis.

References

• BMJ case reports • 2023 • Novel mutation causing Zellweger syndrome. PMID:36931687
• 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
• The EMBO journal • 2009 • Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19. PMID:19197237
• Traffic (Copenhagen, Denmark) • 2012 • The role of conserved PEX3 regions in PEX19-binding and peroxisome biogenesis. PMID:22624858
• Journal of biochemistry • 2017 • Peroxisome biogenesis: a novel inducible PEX19 splicing variant is involved in early stages of peroxisome proliferation. PMID:28391327

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