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Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder
Kim D Falkenberg1, Nancy E Braverman2, Ann B Moser3
1Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
American Journal of Human Genetics
|December 9, 2017
Summary
Allelic expression imbalance (AEI) can cause Zellweger spectrum disorders (ZSDs) by overrepresenting a PEX6 gene mutation. This finding suggests AEI may contribute to other recessive genetic disorders.
Area of Science:
- Genetics
- Molecular Biology
- Cell Biology
Background:
- Zellweger spectrum disorders (ZSDs) are severe genetic conditions impacting peroxisome biogenesis.
- These disorders typically result from recessive mutations in PEX genes, requiring biallelic gene defects.
Purpose of the Study:
- To investigate the genetic basis of apparent dominant ZSD cases.
- To explore the role of allelic expression imbalance (AEI) in PEX6 gene mutations.
Main Methods:
- Genetic analysis of affected individuals and their parents.
- Assessment of PEX6 gene expression and polyadenylation site usage.
- Functional studies using overexpression models.
Main Results:
- Identified seven individuals with apparent dominant ZSD carrying a heterozygous PEX6 mutation (c.2578C>T).
- Demonstrated that allelic expression imbalance (AEI) overrepresented the mutant PEX6 allele in affected individuals.
- Linked AEI to a 3' UTR variant disrupting a polyadenylation site, a phenomenon observed in common PEX6 heterozygotes.
Conclusions:
- Overrepresentation of a pathogenic PEX6 allele due to AEI can cause ZSDs, mimicking dominant inheritance.
- AEI of the PEX6 gene is a significant factor in ZSD pathogenesis.
- This mechanism of AEI potentially explains other autosomal recessive disorders where only one heterozygous pathogenic variant is found.
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