PEX13 and Peroxisome Biogenesis Disorder

PEX13, a peroxisomal membrane protein, is implicated in peroxisome biogenesis disorders that typically follow an autosomal recessive inheritance pattern. Clinical case reports and multi‐patient studies have documented that pathogenic variants in PEX13 disrupt peroxisomal assembly, leading to a spectrum of manifestations including neurological dysfunction, hepatic impairment, and failure to thrive (PMID:37962062).

A notable variant, c.977T>C (p.Ile326Thr), has been identified in affected individuals and is associated with a temperature‐sensitive phenotype. In patients experiencing fever, the mutation leads to protein misfolding and increased protease susceptibility, thereby compromising peroxisomal import of matrix proteins (PMID:16006427).

Multi‐patient studies report approximately 21 unrelated cases worldwide, with segregation analysis in consanguineous families further supporting the autosomal recessive inheritance of the disorder (PMID:37962062). In these patients, diverse variant classes including missense mutations and frameshift changes contribute to the phenotype. The recurrent identification of the c.977T>C variant underscores its clinical relevance.

Genetic evidence reinforces that a broad variant spectrum in PEX13 is causative for peroxisome biogenesis disorders. The observed mutation patterns—comprising both missense and loss‐of‐function alleles—coupled with supportive segregation data, strongly validate the gene–disease association (PMID:37962062).

Functional studies have provided additional support by demonstrating that the mutated PEX13 protein exhibits temperature‐dependent instability and impaired peroxisomal import in patient-derived fibroblasts. Biophysical assays, including circular dichroism and protease digestion, confirm the deleterious impact of the c.977T>C (p.Ile326Thr) mutation on protein folding (PMID:16006427, PMID:10332040).

The integration of clinical, genetic, and experimental data presents a coherent narrative: disruption of PEX13 function due to pathogenic variants leads to compromised peroxisomal assembly and metabolic dysfunction. Although additional variants and functional studies exist, the cumulative evidence robustly supports a strong gene–disease association.

Key Take‑Home: Genetic testing for PEX13 variants is of high clinical utility, enabling accurate diagnosis and informing management strategies for patients with peroxisome biogenesis disorders.

References

• Pediatric Research • 2005 • Molecular mechanism of a temperature‑sensitive phenotype in peroxisomal biogenesis disorder PMID:16006427
• Molecular Genetics & Genomic Medicine • 2024 • Severe Zellweger spectrum disorder due to a novel missense variant in the PEX13 gene: A case report and the literature review PMID:37962062
• Human Molecular Genetics • 1999 • Nonsense and temperature‑sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders PMID:10332040
• Human Molecular Genetics • 2013 • Functional analysis of PEX13 mutation in a Zellweger syndrome spectrum patient reveals novel homooligomerization of PEX13 and its role in human peroxisome biogenesis PMID:23716570

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