Distinguishing PEX2 and PEX16 Gene Variant Severity for Mild, Severe and Atypical Peroxisome Biogenesis Disorders

Authors

Vanessa A Gomez
Oguz Kanca
Sharayu V Jangam
Saurabh Srivastav
Jonathan C Andrews
Michael F Wangler

Language

English

Publication Date

7-1-2025

Journal

Disease Models & Mechanisms

DOI

10.1242/dmm.052258

PMID

40621817

PMCID

PMC12352285

PubMedCentral® Posted Date

7-28-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Peroxisomal biogenesis disorders (PBD) are autosomal recessive diseases caused by mutations in specific PEX genes that impair peroxisome formation, leading to multi-systemic failure. Symptoms vary, even in patients with variants in the same PEX gene. Our goal is to select PEX mutations and use Drosophila to model a severity spectrum based on genotype-phenotype correlations. Utilizing KozakGAL4 (KZ) cassettes, we replaced the coding sequence of Pex with a GAL4 driver, ideal for making 'humanized' flies in which human PEX can replace the fly loss. We generated Pex2KZ and Pex16KZ lines and assessed them in various behavior assays, confirming their severe phenotypes. We performed rescue with human reference, variant PEX2 and PEX16 alleles, and phenotypic rescue was observed when human PEX2Ref or PEX16Ref were expressed in Pex2KZ or Pex16KZ flies, respectively. We identified a severity spectrum for PEX2 and PEX16 alleles, with some missense mutations exhibiting severity comparable to truncations. Alleles linked to mild PBD showed partial rescue, while variants associated with atypical ataxia could fully rescue. Drosophila humanization is an effective method to study the range of severity of PBD.

Keywords

Animals, Humans, Peroxisomal Disorders, Mutation, Drosophila melanogaster, Drosophila Proteins, Membrane Proteins, Phenotype, Alleles, Severity of Illness Index, Genetic Variation, Peroxisomes, Peroxisomal Targeting Signal 2 Receptor, Genetic Association Studies, Peroxisome, Drosophila, PEX2, PEX16, Zellweger, PBD

Published Open-Access

yes

Recommended Citation

Gomez, Vanessa A; Kanca, Oguz; Jangam, Sharayu V; et al., "Distinguishing PEX2 and PEX16 Gene Variant Severity for Mild, Severe and Atypical Peroxisome Biogenesis Disorders" (2025). Duncan NRI Faculty and Staff Publications. 184.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/184