Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy

Kodal, Louise Sloth; Hammer-Hansen, Sophia; Holm-Yildiz, Sonja; Grønskov, Karen; Karstensen, Helena Gásdal; Dysgaard, Tina

doi:10.3389/fneur.2022.1066040

Cited by 6 publications

(4 citation statements)

References 9 publications

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“…Using whole-exome sequencing, we uncovered a homozygous missense mutation in SLC25A46 , in a patient with the Leigh syndrome, an early-onset, fatal neurodegenerative disorder ( Janer et al, 2016 ). Subsequently, 29 patients from 22 families were reported with biallelic missense mutations in SLC25A46 ( Fig 1A ) in an increasingly broad spectrum of neurological disorders that includes progressive myoclonic ataxia, autosomal recessive cerebellar ataxias, pontocerebellar hypoplasia with spinal muscular atrophy (PCH1), and Parkinson’s disease and optic atrophy ( Charlesworth et al, 2016 ; Wan et al, 2016 ; Hammer et al, 2017 ; Nguyen et al, 2017 ; Sulaiman et al, 2017 ; van Dijk et al, 2017 ; Abrams et al, 2018 ; Braunisch et al, 2018 ; Bitetto et al, 2020 ; Ababneh et al, 2021 ; Kodal et al, 2022 ). The onset and course of the disease are highly variable, ranging from fetal death to survival to 50 yr of age.…”

Section: Introductionmentioning

confidence: 99%

The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion

et al. 2023

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Mutations inSLC25A46underlie a wide spectrum of neurodegenerative diseases associated with alterations in mitochondrial morphology. We established an SLC25A46 knock-out cell line in human fibroblasts and studied the pathogenicity of three variants (p.T142I, p.R257Q, and p.E335D). Mitochondria were fragmented in the knock-out cell line and hyperfused in all pathogenic variants. The loss of SLC25A46 led to abnormalities in the mitochondrial cristae ultrastructure that were not rescued by the expression of the variants. SLC25A46 was present in discrete puncta at mitochondrial branch points and tips of mitochondrial tubules, co-localizing with DRP1 and OPA1. Virtually, all fission/fusion events were demarcated by a SLC25A46 focus. SLC25A46 co-immunoprecipitated with the fusion machinery, and loss of function altered the oligomerization state of OPA1 and MFN2. Proximity interaction mapping identified components of the ER membrane, lipid transfer proteins, and mitochondrial outer membrane proteins, indicating that it is present at interorganellar contact sites. SLC25A46 loss of function led to altered mitochondrial lipid composition, suggesting that it may facilitate interorganellar lipid flux or play a role in membrane remodeling associated with mitochondrial fusion and fission.

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Section: Introductionmentioning

confidence: 99%

The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion

et al. 2023

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“…Autosomal-dominant mutations in RAB7 lead to Charcot-Marie-Tooth (CMT) type 2B (Meggouh et al 2006) while mutations of MFN2 cause CMT type 2A. SLC25A46 has also been associated with CMT type 2 and a variety of other neurological disorders, such as optic atrophy and cerebellar atrophy (Abrams et al 2018; Abrams et al 2015; Braunisch et al 2018; Buglo et al 2020; Charlesworth et al 2016; Hammer et al 2017; Kodal et al 2022). SLC25A46 is a mitochondrial outer membrane protein (Abrams et al 2015; Janer et al 2016) and plays an ill- defined role in mitochondrial fusion and fission, interacting with the fusion associated proteins MFN2 and OPA1, while the knock-out of SLC25A46 leads to altered oligomerization states of MFN2 and OPA1 (Schuettpelz et al 2023).…”

Section: Introductionmentioning

confidence: 99%

SLC25A46 is in contact with lysosomes and plays a role in mitochondrial cholesterol homeostasis

Schuettpelz,

Watt,

Antonicka

et al. 2024

Preprint

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Mitochondrial morphology reflects the dynamic equilibrium between fusion and fission events, controlled by cellular signaling. A cytoprotective response known as stress-induced mitochondrial hyperfusion (SIMH) is triggered by nutrient starvation and we show that the outer mitochondrial membrane protein SLC25A46 is required for this response. To unravel the cellular mechanisms involved, we conducted transcriptomic analysis on control human fibroblasts and SLC25A46 knock-out cells. Our analysis revealed a remarkable divergence in the transcriptional profile of proteins associated with lysosomal function and cholesterol binding and synthesis. Further investigations using live-cell imaging validated the presence of SLC25A46 at the majority of mitochondria-lysosome contact sites. Since mitochondria-lysosome contacts are linked to cholesterol transport, we investigated the involvement of SLC25A46 in cholesterol trafficking. The SLC25A46 knock-out cell line exhibited a decrease in mitochondrial cholesterol content and distinct alterations were observed in the pattern of cholesterol trafficking compared to control. Cholesterol supplementation in the SLC25A46 knock-out cell line rescued the mitochondrial fragmentation phenotype and restored the SIMH response, suggesting a role for SLC25A46 in maintaining mitochondrial cholesterol homeostasis.

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“…A population-based phasing strategy leverages the information of co-occurrences of variants across multiple hundreds to thousands of individuals 13 . Thus, while this strategy can easily phase entire chromosome arms, it can only do so on common SNPs in the population, and therefore misses the rare and likely disease-causing variants 14 , 15 . Another strategy, trio-phasing, involves obtaining parental information and using it to phase a single nucleotide variant (SNV) based on the co-occurrence of the parents 16 .…”

Section: Introductionmentioning

confidence: 99%

MethPhaser: methylation-based long-read haplotype phasing of human genomes

Fu,

Aganezov,

Mahmoud

et al. 2024

Nat Commun

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The assignment of variants across haplotypes, phasing, is crucial for predicting the consequences, interaction, and inheritance of mutations and is a key step in improving our understanding of phenotype and disease. However, phasing is limited by read length and stretches of homozygosity along the genome. To overcome this limitation, we designed MethPhaser, a method that utilizes methylation signals from Oxford Nanopore Technologies to extend Single Nucleotide Variation (SNV)-based phasing. We demonstrate that haplotype-specific methylations extensively exist in Human genomes and the advent of long-read technologies enabled direct report of methylation signals. For ONT R9 and R10 cell line data, we increase the phase length N50 by 78%-151% at a phasing accuracy of 83.4-98.7% To assess the impact of tissue purity and random methylation signals due to inactivation, we also applied MethPhaser on blood samples from 4 patients, still showing improvements over SNV-only phasing. MethPhaser further improves phasing across HLA and multiple other medically relevant genes, improving our understanding of how mutations interact across multiple phenotypes. The concept of MethPhaser can also be extended to non-human diploid genomes. MethPhaser is available at https://github.com/treangenlab/methphaser.

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Case report: A novel variant in SLC25A46 causing sensorimotor polyneuropathy and optic atrophy

Cited by 6 publications

References 9 publications

The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion

The role of the mitochondrial outer membrane protein SLC25A46 in mitochondrial fission and fusion

SLC25A46 is in contact with lysosomes and plays a role in mitochondrial cholesterol homeostasis

MethPhaser: methylation-based long-read haplotype phasing of human genomes

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