PEX13 – Zellweger Spectrum Disorders

PEX13 (HGNC:8855) encodes a peroxisomal membrane docking factor essential for PTS1 receptor import. Biallelic PEX13 variants cause autosomal recessive Zellweger spectrum disorders characterized by neonatal hypotonia, seizures, hepatic dysfunction, failure to thrive, developmental regression, and progressive spasticity. Biochemical hallmarks include elevated very long-chain fatty acids, phytanic acid, and pipecolic acid, reflecting peroxisomal dysfunction.

In a Chinese infant with severe ZSD, a novel homozygous missense variant c.493G>C (p.Ala165Pro) was identified by WES, presenting hypotonia, seizures, hepatic dysfunction, and failure to thrive; VLCFA profiling confirmed the diagnosis (PMID:37962062).

A neonatal adrenoleukodystrophy patient exhibited a temperature-sensitive phenotype due to c.977T>C (p.Ile326Thr) in the SH3 domain of PEX13, with peroxisomal import defects at 37 °C and restored function at 30 °C, revealing a folding instability mechanism (PMID:16006427).

Multi-patient studies first defined complementation group H in two unrelated patients: one with a homozygous nonsense variant p.Trp234Ter causing classical Zellweger syndrome and another with homozygous p.Ile326Thr leading to a milder NALD, both rescued by wild-type cDNA expression in deficient cells (PMID:10332040).

An Orphanet Rare Diseases study reported five families carrying biallelic PEX13 variants, including a recurrent c.880C>T (p.Arg294Trp), with heterogeneous clinical presentations; computational and fibroblast complementation analyses implicated disrupted PEX13 homodimerization and PEX13/PEX14 translocation module instability (PMID:35854306).

Functional assessments demonstrate that p.Ile326Thr exhibits increased protease susceptibility, reduced thermal stability, and unfolding propensity in urea denaturation assays (PMID:16006427); p.Trp313Gly disrupts PEX13 homooligomerization and PTS1 import in live-cell FRET and rescue experiments (PMID:23716570); and a conditional Pex13 brain-specific knockout mouse model exhibits serotonergic neuron deficiency and gliosis mirroring human neuropathology (PMID:24881576).

Collectively, nine unrelated probands across eight families with AR inheritance and concordant functional data support a Strong gene–disease association. The loss-of-function mechanism via misfolding and impaired homooligomerization leads to defective peroxisomal matrix import. PEX13 mutation analysis is clinically useful for definitive diagnosis, prognosis, and genetic counseling in Zellweger spectrum disorders.

References

• Pediatric research • 2005 • Molecular mechanism of a temperature-sensitive phenotype in peroxisomal biogenesis disorder. PMID:16006427
• Human molecular genetics • 1999 • Nonsense and temperature-sensitive mutations in PEX13 are the cause of complementation group H of peroxisome biogenesis disorders. PMID:10332040
• Orphanet journal of rare diseases • 2022 • Genotype-phenotype correlations and disease mechanisms in PEX13-related Zellweger spectrum disorders. PMID:35854306
• 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 • 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
• Neuroscience • 2014 • Central serotonergic neuron deficiency in a mouse model of Zellweger syndrome. PMID:24881576

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