title: Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder.
abstract: 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.
authors.affiliation: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands.|School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: I
authors.initials: I
authors.lastname: Boesten
authors.affiliation: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: D M E I
authors.initials: DM
authors.lastname: Hellebrekers
authors.affiliation: Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: Mulder-den Hartog
authors.affiliation: Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: I F M
authors.initials: IF
authors.lastname: de Coo
authors.affiliation: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands.|School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: H J M
authors.initials: HJ
authors.lastname: Smeets
authors.affiliation: Department of Clinical Genetics, Unit Clinical Genomics, Maastricht University Medical Centre, Maastricht, The Netherlands.|School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre, Maastricht, The Netherlands.|Maastricht Center for Systems Biology (MaCSBio), Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Gerards
mesh_terms: D001483:Base Sequence; D003241:Consanguinity; D059472:Exome / Q000235:genetics; D005091:Exons / Q000235:genetics; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D010290:Parents; D010375:Pedigree; D028061:Phosphate Transport Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D024101:Mitochondrial Proteins; D028061:Phosphate Transport Proteins; D022821:RNA Splice Sites; C584459:SLC25A46 protein, human
keywords: SLC25A46; cerebellar atrophy; exome sequencing; mitochondrial dynamics; optic atrophy