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Recessive MECR pathogenic variants cause an LHON-like optic neuropathy
Claudio Fiorini1, Andrea Degiorgi2, Maria Lucia Cascavilla3
1Programma di Neurogenetica, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy.
Journal of Medical Genetics
|September 21, 2023
Summary
MECR gene variants cause Leber hereditary optic neuropathy (LHON)-like symptoms. This study reveals impaired mitochondrial fatty acid synthesis as a new LHON mechanism.
Area of Science:
- Genetics
- Mitochondrial Biology
- Neuro-ophthalmology
Background:
- Leber hereditary optic neuropathy (LHON) is a mitochondrial disorder causing retinal ganglion cell degeneration, typically linked to mitochondrial DNA mutations.
- LHON has also been associated with nuclear gene variants, including MCAT, which is involved in mitochondrial fatty acid synthesis (mtFAS).
- MECR, encoding mitochondrial trans-2-enoyl-CoA reductase, is crucial for mtFAS; its mutations cause a childhood-onset disorder with optic atrophy.
Purpose of the Study:
- To investigate the genetic basis of LHON-like optic neuropathy in two sisters with sudden visual loss.
- To elucidate the functional consequences of a candidate MECR variant on mitochondrial function and cellular stress response.
Main Methods:
- Whole exome sequencing identified a homozygous MECR variant in affected sisters.
- The identified MECR variant was modeled in yeast to assess mitochondrial dysfunction, including oxidative growth, oxygen consumption, and protein levels.
- Protein lipoylation, response to oxidative stress (H2O2), and the effect of lipoic acid supplementation were evaluated in the yeast model.
Main Results:
- Both sisters harbored a homozygous pathogenic MECR variant (p.Arg258Trp).
- The MECR-R258W mutation in yeast led to reduced growth, decreased oxygen consumption, and significantly lower MECR protein levels, suggesting structural destabilization.
- The yeast mutant exhibited impaired lipoylation and increased sensitivity to oxidative stress, with partial rescue by lipoic acid.
Conclusions:
- This study reports the first family with a homozygous MECR variant causing an LHON-like optic neuropathy.
- The findings link MECR mutations to LHON, reinforcing the role of impaired mitochondrial fatty acid synthesis as a novel pathogenic mechanism in LHON.
- This expands the genetic spectrum of LHON and highlights mtFAS defects as a potential cause of optic neuropathies.
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