Journal
CLINICAL GENETICS
Volume 91, Issue 1, Pages 121-125Publisher
WILEY-BLACKWELL
DOI: 10.1111/cge.12774
Keywords
optic atrophy; SLC25A46; cerebellar atrophy; exome sequencing; mitochondrial dynamics
Categories
Funding
- Alma in Silico project - Interreg IV European funds
- Walloon Region
- North Rhine Westphalia
- Flemish Community
- Belgian Province of Limburg
- Dutch Province of Limburg
- University of Maastricht
- Prinses Beatrix Spierfonds [W.OR11-24]
- join4energy
- University of Liege
- Stichting Metakids
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The inherited optic neuropathies comprise a group of genetically heterogeneous disorders causing optic nerve dysfunction. In some cases, optic neuropathies are associated with cerebellar atrophy which mainly affects the vermis. Here, we describe a Moroccan girl of consanguineous parents with optic atrophy and cerebellar atrophy. Exome sequencing revealed a novel homozygous mutation (c.283+3G>T) in the donor splice site for exon 1 of SLC25A46. RNA analysis revealed that an alternative splice site within exon 1 was used leading to a premature termination codon within exon 2. SLC25A46 mRNA expression showed there is no wild-type transcript present in the patient and the mutant transcript does not undergo nonsense-mediated mRNA decay. Futhermore, we observed c.283+ 3G>T SLC25A46 mutation induces mitochondrial fragmentation. An additional 10 patients with optic atrophy and cerebellar atrophy, which were negative for mtDNA and OPA1 variants, were tested for pathogenic mutations in the SLC25A46 gene. However, no additional variants were identified. Our findings confirm the recent report of pathogenic SLC25A46 mutations as a novel cause for optic atrophy spectrum disorder.
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