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.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02059-z) contains supplementary material, which is available to authorized users.

Characterization of a novel variant in the HR1 domain ofMFN2in a patient with ataxia, optic atrophy and sensorineural hearing loss

“…The reduced mtDNA copy number and nucleoid number observed in patient fibroblasts is consistent with impaired mitochondrial fusion in these cells, as reduced copy number is proposed to be due to inefficient fusion-dependent distribution of the mtDNA replication machinery (19). Surprisingly, we also observed slightly smaller nucleoids in patient cells, an unexpected finding given that impaired mitochondrial fusion has previously been linked to enlarged mitochondrial nucleoids (19,21,64). However, it should be noted that it is not clear why nucleoid size increases in response impaired fusion.…”

Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance

“…It has been reported that TFAM and mtDNA stabilize each other by binding to each other; thus, mtDNA can only be stably maintained in the form of nucleoid structures within the mitochondria, whereas both naked DNA and free TFAM in mitochondria are unstable and can be rapidly degraded 34 . During disease development, decreased TFAM levels may impair the interaction of TFAM with mtDNA and thus reduce the number of nucleoids and cause the formation of aberrant clusters; this, in turn, results in depletion of mtDNA and inhibition of mitochondrial transcription 55 , 56 . Indeed, we found that TFAM knockdown alone was sufficient to induce mtROS production, aberrant packaging of mtDNA nucleoids, and mitochondrial respiratory defects in TECs.…”

Channelopathies Are a Frequent Cause of Genetic Ataxias Associated with Cerebellar Atrophy

“…Patients from 15 families were previously published as part of a brief report on utility of WES in pediatric-onset ataxia and in separate publications reporting novel genes or expanding the phenotypic spectrum associated with known genes. [14][15][16][17][18][19][20][21][22][23] WES was performed on total genomic DNA from the 92 participants. DNA was extracted from peripheral blood following standard procedures.…”

“…Patients from 15 families were previously published as part of a brief report on utility of WES in pediatric‐onset ataxia and in separate publications reporting novel genes or expanding the phenotypic spectrum associated with known genes 14–23 …”