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Published on: October 10, 2025
Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy
Xiaowu Gai1, Daniele Ghezzi, Mark A Johnson
1Department of Molecular Pharmacology and Therapeutics, Loyola University Stritch School of Medicine, Maywood, IL 60153, USA.
American Journal of Human Genetics
|September 3, 2013
Summary
Mutations in the FBXL4 gene cause early-onset mitochondrial encephalomyopathy, leading to severe neurological and multi-systemic symptoms. This research identifies FBXL4 as a key factor in mitochondrial function and DNA maintenance.
Area of Science:
- Genetics
- Mitochondrial Biology
- Neuroscience
Background:
- Mitochondrial OXPHOS-enzyme deficiencies cause severe early-onset diseases.
- Genetic factors underlying these deficiencies are not fully understood.
Purpose of the Study:
- To identify genetic causes of combined mitochondrial OXPHOS-enzyme deficiencies.
- To elucidate the role of FBXL4 in mitochondrial function and disease.
Main Methods:
- Whole-exome sequencing and autozygosity mapping in affected families.
- Clinical and biochemical analyses of patient tissues (muscle, fibroblasts).
- Cellular studies on mitochondrial network and DNA content.
Main Results:
- Nine disease-segregating FBXL4 mutations were identified in seven families.
- Patients presented with early-onset lactic acidemia, hypotonia, developmental delay, and encephalomyopathy.
- FBXL4 protein localizes to mitochondria and is crucial for bioenergetic homeostasis and mtDNA maintenance.
Conclusions:
- FBXL4 mutations are a significant cause of early-infantile mitochondrial encephalomyopathy.
- FBXL4 plays a critical role in mitochondrial energy production and mtDNA stability.
- FBXL4 is a novel gene implicated in inherited mitochondrial disorders.
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