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PEX14 – Peroxisome Biogenesis Disorder

Peroxisome biogenesis disorder due to PEX14 mutations presents primarily as Zellweger spectrum disorders with variable age of onset. A single autosomal recessive case exhibited late‐onset ZS characterized by progressive loss of visual acuity and history of ocular medulloepithelioma, leading to diagnosis at 9 years of age (PMID:30224891). More recently, two unrelated patients with autosomal dominant ZSD were identified carrying heterozygous de novo PEX14 splice-site variants (c.585+1G>T) causing C-terminal truncations and exerting a dominant-negative effect on peroxisome import through aberrant pexophagy (2 probands; PMID:37493040). No additional familial segregation data are available.

Biochemical and cell-based assays demonstrate that the N-terminal domain of PEX14 forms a three-helical fold essential for high-affinity binding to PEX5 and PEX19, mediating peroxisomal matrix and membrane protein import, respectively (PMID:10026185; PMID:19197237). Disruption of PEX14 interactions or expression leads to loss of PTS1/PTS2 import and peroxisome degradation, consistent with disease phenotypes. Taken together, genetic evidence remains limited (three probands, no segregation) but is supported by moderate functional concordance. Key Take-home: PEX14 variants cause peroxisome biogenesis disorder via loss-of-function or dominant-negative mechanisms, underscoring its clinical utility in molecular diagnosis.

References

  • Saudi journal of ophthalmology • 2018 • A clinical case of Zellweger syndrome in a patient with a previous history of ocular medulloepithelioma PMID:30224891
  • 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
  • The EMBO journal • 2009 • Structural basis for competitive interactions of Pex14 with the import receptors Pex5 and Pex19 PMID:19197237

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three probands (one AR, two AD de novo) with limited segregation, but supportive functional data

Genetic Evidence

Limited

Variants identified in three unrelated patients (1 AR PEX14 case [PMID:30224891]; 2 de novo AD cases [PMID:37493040]); no segregation data

Functional Evidence

Moderate

Structural docking and binding assays demonstrating PEX14 interaction with PEX5 and PEX19; cell models showing impaired import of matrix proteins (PMID:10026185; PMID:19197237)