Related Experiment Video
Updated: Jul 25, 2025
Multi-Photon Time Lapse Imaging to Visualize Development in Real-time: Visualization of Migrating Neural Crest Cells in Zebrafish Embryos
Published on: August 9, 2017
Novel PEX1 mutations in fibroblasts from children with Zellweger spectrum disorders exhibit temperature sensitive
Jao-Shwann Liang1, Kun-Long Hung2, Li-Ju Lin3
1Departments of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Nursing, Asia Eastern University of Science and Technology, New Taipei City, Taiwan.
Insights
Zellweger spectrum disorders (ZSD) result from peroxisome biogenesis defects. Novel PEX1 mutations, including a temperature-sensitive variant, offer insights into ZSD
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Zellweger spectrum disorders (ZSD) are rare genetic conditions affecting peroxisome function.
- These disorders stem from mutations in peroxisome biogenesis factor (PEX) genes, disrupting protein transport.
- Impaired peroxisomal protein import affects various metabolic pathways and cellular functions.
Purpose of the Study:
- To describe novel mutations in PEX1 associated with Zellweger spectrum disorders.
- To investigate the functional characteristics of a novel temperature-sensitive PEX1 mutation (p.Ile989Thr).
- To explore the molecular mechanisms underlying clinical variability in ZSD.
Main Methods:
- Genetic analysis of four ZSD patients, including homozygotic twins.
- Identification and characterization of novel PEX1 mutations (nonsense, frameshift, splicing).
- Functional assessment of the p.Ile989Thr PEX1 mutant, including temperature sensitivity.
- Transcriptome profiling under varying temperature conditions.
Main Results:
- Three novel mutations in PEX1 were identified in ZSD patients.
- The p.Ile989Thr PEX1 mutant demonstrated temperature-sensitive properties, correlating with milder ZSD.
- The p.Ile989Thr mutant's characteristics differ from previously identified temperature-sensitive mutants like p.Gly843Asp.
- Transcriptome analysis provided insights into the molecular behavior of the p.Ile989Thr mutant.
Conclusions:
- Novel PEX1 mutations contribute to the genetic landscape of Zellweger spectrum disorders.
- The temperature-sensitive p.Ile989Thr mutation offers a model for understanding genotype-phenotype correlations in ZSD.
- Further research into molecular mechanisms is crucial for explaining ZSD clinical heterogeneity.
Abstract:
Zellweger spectrum disorders (ZSD) are rare autosomal recessive disorders caused by defects in peroxisome biogenesis factor (PEX; peroxin) genes leading to impaired transport of peroxisomal proteins with peroxisomal targeting signals (PTS). Four patients, including a pair of homozygotic twins, diagnosed as ZSD by genetic study with different clinical presentations and outcomes as well as various novel mutations are described here. A total of 3 novel mutations, including a nonsense, a frameshift, and a splicing mutation, in PEX1 from ZSD patients were identified and unequivocally confirmed that the p.Ile989Thr mutant PEX1 exhibited temperature-sensitive characteristics and is associated with milder ZSD. The nature of the p.Ile989Thr mutant exhibited different characteristics from that of the other previously identified temperature-sensitive p.Gly843Asp PEX1 mutant. Transcriptome profiles under nonpermissive vs. permissive conditions were explored to facilitate the understanding of p.Ile989Thr mutant PEX1. Further investigation of molecular mechanisms may help to clarify potential genetic causes that could modify the clinical presentation of ZSD.
Related Concept Videos
01:33Pleiotropy
01:27Protein Import into the Peroxisomes
Peroxisomal Protein Import:
Peroxisomes lack the genetic machinery required to code for their own proteins. Hence, most peroxisomal membrane, lumenal and transmembrane proteins are synthesized in the cytoplasm or ER and transported to the peroxisome...