PEX14 – Zellweger spectrum disorders

PEX14 encodes a central peroxisomal membrane protein essential for matrix protein import. Bi‐allelic and de novo variants in PEX14 have been implicated in Zellweger spectrum disorders (ZSD), a peroxisome biogenesis disorder characterized by hypotonia, liver dysfunction, and neuro‐sensory deficits. Both autosomal recessive and rare autosomal dominant presentations have been documented, with functional studies confirming loss of peroxisome import and dominant‐negative pexophagy mechanisms.

Early reports described two unrelated patients with bi‐allelic PEX14 variants presenting in infancy. One patient harbored a genomic deletion leading to exon 3 skipping and a frameshift (c.85-?_170+?del) resulting in p.Ile29_Lys56del;Gly57GlyfsTer2, with restoration of peroxisomal matrix import upon wild‐type PEX14 transfection (PMID:21686775). A second Japanese infant carried a homozygous nonsense variant c.538C>T (p.Gln180Ter), with classic hypotonia, failure to thrive, demyelination, rickets, and eventual liver failure (PMID:26627464).

More recently, two unrelated patients with autosomal dominant ZSD were identified, each carrying a de novo splice‐region variant (c.585+1G>T) or a synonymous change (c.585G>A) leading to aberrant mRNA splicing. The resulting C‐terminally truncated PEX14 proteins exert dominant‐negative effects by promoting pexophagy and loss of matrix protein import; inhibition of autophagy or NBR1 knockdown restored peroxisomal function in fibroblasts (PMID:37493040).

The spectrum of pathogenic alleles in PEX14 now includes large exon deletions, nonsense, canonical splice, and de novo mis‐splicing variants. Functional data from patient fibroblasts demonstrate rescue of peroxisomal import in recessive cases and restoration of peroxisome homeostasis upon autophagy inhibition in dominant cases. Structural studies of the PEX5–PEX14 interaction reveal a high‐affinity binding interface that underlies import efficiency (PMID:10026185).

Together, genetic and experimental evidence support a Moderate clinical validity for the PEX14–ZSD association: four unrelated probands (two bi‐allelic, two de novo) with concordant functional rescue and dominant‐negative assays. Additional case series and long‐term follow‐up could elevate this classification. PEX14 sequencing and functional complementation assays have demonstrable utility in confirming ZSD diagnoses and guiding family counseling.

Key Take-home: PEX14 variant analysis, supported by peroxisomal import rescue and autophagy modulation assays, is clinically actionable for diagnosing both recessive and dominant forms of Zellweger spectrum disorders.

References

• BMJ case reports • 2009 • Identification of a novel PEX14 mutation in Zellweger syndrome. PMID:21686775
• Pediatrics International • 2015 • First Japanese case of Zellweger syndrome with a mutation in PEX14. PMID:26627464
• Genetics in Medicine • 2023 • Autosomal dominant Zellweger spectrum disorder caused by de novo variants in PEX14 gene. PMID:37493040
• The Journal of Biological Chemistry • 1999 • Recombinant human peroxisomal targeting signal receptor PEX5. Structural basis for interaction of PEX5 with PEX14. PMID:10026185

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