| Title: |
MSTO1 Mutations Cause Mtdna Depletion, Manifesting As Muscular Dystrophy With Cerebellar Involvement |
| Authors: |
Donkervoort, S; Sabouny, R; Yun, P; Gauquelin, L; Chao, KR; Hu, Y; AI Khatib, I; Topf, A; Mohassel, P; Cummings, BB; Kaur, R; Saade, D; Moore, SA; Waddell, LB; Farrar, MA; Goodrich, JK; Uapinyoying, P; Chan, SHS; Javed, A; Leach, ME; Karachunski, P; Dalton, J; Medne, L; Harper, A; Thompson, C; Thiffault, I; Specht, S; Lamont, RE; Saunders, C; Racher, H; Bernier, FP; Mowat, D; Witting, N; Vissing, J; Hanson, R; Coffman, KA; Hainlen, M; Parboosingh, JS; Carnevale, A; Yoon, G; Schnur, RE; Care4Rare Canada Consortium; Boycott, KM; Mah, JK; Straub, V; Reghan Foley, A; Innes, AM; Bönnemann, CG; Shutt, TE |
| Publisher Information: |
//link.springer.de/link/service/journals/00401/index.htm; Germany |
| Publication Year: |
2019 |
| Collection: |
University of Hong Kong: HKU Scholars Hub |
| Subject Terms: |
MSTO1; Mitochondrial fusion; Cerebellar atrophy; Muscular dystrophy; MtDNA depletion |
| Description: |
MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Acta Neuropathologica; 1031; 305880; 305882; WOS:000496124600007; 1013; https://hub.hku.hk/handle/10722/277185; 138 |
| DOI: |
10.1007/s00401-019-02059-z |
| Availability: |
https://hub.hku.hk/handle/10722/277185; https://doi.org/10.1007/s00401-019-02059-z |
| Rights: |
This is a post-peer-review, pre-copyedit version of an article published in [Acta Neuropathologica]. The final authenticated version is available online at: http://dx.doi.org/10.1007/s00401-019-02059-z ; This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. |
| Accession Number: |
edsbas.55AC9C79 |
| Database: |
BASE |