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Updated: Aug 7, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
The 13042G --> A/ND5 mutation in mtDNA is pathogenic and can be associated also with a prevalent ocular phenotype
M L Valentino1, P Barboni, C Rengo
1Dipartimento di Scienze Neurologiche, Università di Bologna, Via Ugo Foscolo 7, 40123, Bologna, Italy.
Background:
Overlapping phenotypes including LHON, MELAS, and Leigh syndrome have recently been associated with numerous mtDNA point mutations in the ND5 gene of complex I, now considered a mutational hot spot.
Objective:
To identify the mtDNA defect in a family with a prevalent ocular phenotype, including LHON-like optic neuropathy, retinopathy, and cataract, but characterised also by strokes, early deaths, and miscarriages on the maternal line.
Results:
Sequencing of the entire mitochondrial genome from the proband's muscle DNA identified the heteroplasmic 13042G-->A transition, which was previously described only once in a patient with a different mitochondrial disease. This mutation fulfils the major pathogenic criteria, inducing an amino acid change (A236T) at an invariant position in a highly conserved domain of the ND5 gene. Phosphorus magnetic resonance spectroscopy in the proband disclosed an in vivo brain and skeletal muscle energy metabolism deficit.
Conclusions:
These findings conclusively establish the pathogenic role of the 13042G-->A mutation and underscore its variable clinical expression.
Insights
A novel mitochondrial DNA (mtDNA) mutation, 13042G-->A in the ND5 gene, causes a range of symptoms including optic neuropathy and strokes. This finding highlights the ND5 gene as a hotspot for mitochondrial diseases with varied clinical presentations.
Area of Science:
- Genetics
- Mitochondrial Biology
- Neurogenetics
Background:
- Mitochondrial DNA (mtDNA) point mutations in the ND5 gene of complex I are associated with overlapping phenotypes like LHON, MELAS, and Leigh syndrome.
- The ND5 gene is recognized as a mutational hotspot due to numerous associated mtDNA point mutations.
Purpose of the Study:
- To identify the specific mtDNA defect in a family exhibiting a predominant ocular phenotype (LHON-like optic neuropathy, retinopathy, cataract).
- To investigate the genetic cause of severe systemic manifestations including strokes, early deaths, and miscarriages observed in the maternal line.
Main Methods:
- Mitochondrial genome sequencing of proband's muscle DNA.
- Analysis of mutation pathogenicity based on established criteria.
- In vivo assessment of energy metabolism using phosphorus magnetic resonance spectroscopy.
Main Results:
- The heteroplasmic 13042G-->A transition in the ND5 gene was identified in the proband.
- This mutation results in an A236T amino acid change at a conserved position within the ND5 gene.
- Phosphorus magnetic resonance spectroscopy revealed energy metabolism deficits in the brain and skeletal muscle of the proband.
Conclusions:
- The 13042G-->A mutation is conclusively established as pathogenic.
- The study underscores the significant clinical variability associated with this ND5 gene mutation.
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