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MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement

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Harvard

Donkervoort, S, Sabouny, R, Yun, P, Gauquelin, L, Chao, KR, Hu, Y, Al Khatib, I, Töpf, 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, Boycott, KM, Mah, JK, Straub, V, Foley, AR, Innes, AM, Bönnemann, CG, Shutt, TE & Care4Rare Canada Consortium 2019, 'MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement' Acta Neuropathologica, vol. 138, no. 6, pp. 1013-1031. https://doi.org/10.1007/s00401-019-02059-z

APA

Donkervoort, S., Sabouny, R., Yun, P., Gauquelin, L., Chao, K. R., Hu, Y., ... Care4Rare Canada Consortium (2019). MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. Acta Neuropathologica, 138(6), 1013-1031. https://doi.org/10.1007/s00401-019-02059-z

CBE

Donkervoort S, Sabouny R, Yun P, Gauquelin L, Chao KR, Hu Y, Al Khatib I, Töpf 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, Boycott KM, Mah JK, Straub V, Foley AR, Innes AM, Bönnemann CG, Shutt TE, Care4Rare Canada Consortium. 2019. MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. Acta Neuropathologica. 138(6):1013-1031. https://doi.org/10.1007/s00401-019-02059-z

MLA

Vancouver

Author

Donkervoort, S ; Sabouny, R ; Yun, P ; Gauquelin, L ; Chao, K R ; Hu, Y ; Al Khatib, I ; Töpf, A ; Mohassel, P ; Cummings, B B ; Kaur, R ; Saade, D ; Moore, S A ; Waddell, L B ; Farrar, M A ; Goodrich, J K ; Uapinyoying, P ; Chan, S H S ; Javed, A ; Leach, M E ; Karachunski, P ; Dalton, J ; Medne, L ; Harper, A ; Thompson, C ; Thiffault, I ; Specht, S ; Lamont, R E ; Saunders, C ; Racher, H ; Bernier, F P ; Mowat, D ; Witting, N ; Vissing, J ; Hanson, R ; Coffman, K A ; Hainlen, M ; Parboosingh, J S ; Carnevale, A ; Yoon, G ; Schnur, R E ; Boycott, K M ; Mah, J K ; Straub, V ; Foley, A Reghan ; Innes, A M ; Bönnemann, C G ; Shutt, T E ; Care4Rare Canada Consortium. / MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement. In: Acta Neuropathologica. 2019 ; Vol. 138, No. 6. pp. 1013-1031.

Bibtex

@article{4f19ed6aef5f47b799a4810d1375aa6f,
title = "MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement",
abstract = "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 impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.",
author = "S Donkervoort and R Sabouny and P Yun and L Gauquelin and Chao, {K R} and Y Hu and {Al Khatib}, I and A T{\"o}pf and P Mohassel and Cummings, {B B} and R Kaur and D Saade and Moore, {S A} and Waddell, {L B} and Farrar, {M A} and Goodrich, {J K} and P Uapinyoying and Chan, {S H S} and A Javed and Leach, {M E} and P Karachunski and J Dalton and L Medne and A Harper and C Thompson and I Thiffault and S Specht and Lamont, {R E} and C Saunders and H Racher and Bernier, {F P} and D Mowat and N Witting and J Vissing and R Hanson and Coffman, {K A} and M Hainlen and Parboosingh, {J S} and A Carnevale and G Yoon and Schnur, {R E} and Boycott, {K M} and Mah, {J K} and V Straub and Foley, {A Reghan} and Innes, {A M} and B{\"o}nnemann, {C G} and Shutt, {T E} and {Care4Rare Canada Consortium}",
year = "2019",
month = "12",
doi = "10.1007/s00401-019-02059-z",
language = "English",
volume = "138",
pages = "1013--1031",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer",
number = "6",

}

RIS

TY - JOUR

T1 - MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement

AU - Donkervoort, S

AU - Sabouny, R

AU - Yun, P

AU - Gauquelin, L

AU - Chao, K R

AU - Hu, Y

AU - Al Khatib, I

AU - Töpf, A

AU - Mohassel, P

AU - Cummings, B B

AU - Kaur, R

AU - Saade, D

AU - Moore, S A

AU - Waddell, L B

AU - Farrar, M A

AU - Goodrich, J K

AU - Uapinyoying, P

AU - Chan, S H S

AU - Javed, A

AU - Leach, M E

AU - Karachunski, P

AU - Dalton, J

AU - Medne, L

AU - Harper, A

AU - Thompson, C

AU - Thiffault, I

AU - Specht, S

AU - Lamont, R E

AU - Saunders, C

AU - Racher, H

AU - Bernier, F P

AU - Mowat, D

AU - Witting, N

AU - Vissing, J

AU - Hanson, R

AU - Coffman, K A

AU - Hainlen, M

AU - Parboosingh, J S

AU - Carnevale, A

AU - Yoon, G

AU - Schnur, R E

AU - Boycott, K M

AU - Mah, J K

AU - Straub, V

AU - Foley, A Reghan

AU - Innes, A M

AU - Bönnemann, C G

AU - Shutt, T E

AU - Care4Rare Canada Consortium

PY - 2019/12

Y1 - 2019/12

N2 - 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 impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

AB - 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 impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

U2 - 10.1007/s00401-019-02059-z

DO - 10.1007/s00401-019-02059-z

M3 - Journal article

VL - 138

SP - 1013

EP - 1031

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 6

ER -

ID: 58349947