Novel Biallelic Variants in MSTO1 Associated with Mitochondrial Myopathy
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Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 1 Novel biallelic variants in MSTO1 associated with mitochondrial myopathy 2 3 Laura Schultz-Rogers1, Alejandro Ferrer1, Nikita R. Dsouza2, Michael T. Zimmermann2,3, Benn 4 E. Smith4, Eric W. Klee1,5, Radhika Dhamija6 5 6 1Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905 USA 7 2Bioinformatics Research and Development Laboratory, Genomics Sciences and Precision 8 Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA 9 3Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI 10 53226, USA 11 4Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259 USA 12 5Department of Clinical Genomics, Mayo Clinic, Rochester, MN, 55905 USA 13 6Department of Medical Genetics, Mayo Clinic, Phoenix, AZ, 85054 USA 14 Corresponding author’s email: [email protected] 15 16 HPO TERMS: 17 Hypotonia, early HP:0008947; Restrictive lung disease HP:0002091; Elevated creatine kinase 18 HP:0003236; Delayed gross motor development HP:0002194; Speech articulation difficulties 19 HP:0009088; Dysphagia HP:0002015; Waddling gait HP:0002515; Pectus excavatum 20 HP:0000767; Lumbar kyphosis HP:0008454; EMG: myopathic abnormalities HP:0003458 21 22 SHORT RUNNING TITLE: Novel biallelic variants in MSTO1 myopathy 23 24 25 26 Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 27 ABSTRACT 28 Mitochondrial disorders are caused by nuclear and mitochondrial pathogenic variants 29 leading to defects in mitochondrial function and cellular respiration. Recently, the nuclear- 30 encoded mitochondrial fusion gene MSTO1 (Misato 1) has been implicated in mitochondrial 31 myopathy and ataxia. Here we report on a 30 year old man presenting with a maternally 32 inherited NM_018116.3:c.651C>G, p.F217L missense variant as well as a paternally inherited 33 arr[GRCh37] 1q22(155581773_155706887)x1 deletion encompassing exons 7-14 of MSTO1. 34 His phenotype included muscle weakness, hypotonia, early motor developmental delay, pectus 35 excavatum, and scoliosis. Testing revealed elevated plasma creatine kinase, and 36 electromyogram results were consistent with longstanding generalized myopathy. These 37 phenotypic features overlap well with previously reported patients harboring biallelic MSTO1 38 variants. Additionally, our patient presents with dysphagia and restrictive lung disease, not 39 previously reported for MSTO1-associated disorders. The majority of patients with disease 40 associated variants in MSTO1 present with biallelic variants suggesting autosomal recessive 41 inheritance, however one family has been reported with a single variant and presumed 42 autosomal dominant inheritance. The pattern of inheritance we observed is consistent with the 43 majority of previous reports suggesting an autosomal recessive disorder. We add to our 44 knowledge of the syndrome caused by variants in MSTO1 and provide additional evidence 45 supporting autosomal recessive inheritance. We also describe phenotypic features not reported 46 in previous cases, although further research is needed to confirm they are associated with 47 defects in MSTO1. 48 49 INTRODUCTION 50 Mitochondrial dysfunction leads to a diverse array of disorders most often characterized 51 by myopathic and neurologic symptoms (Chinnery 1993). As the mitochondria are essential for 52 normal aerobic metabolism, tissues and organs with high energy demands such as skeletal Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 53 muscle are particularly sensitive to mitochondrial disruption (Wallace 1999). Damaging variants 54 in over 1000 nuclear encoded and mitochondrial genes can affect respiratory chain complexes, 55 mtDNA replication and maintenance, and dynamic fusion and fission processes. Fusion helps 56 maintain a healthy population of mitochondria by distributing mtDNA and metabolites and 57 eliminating damaged mitochondria through mitophagy (for review see (El-Hattab et al. 2018)). 58 MSTO1 (Misato 1) is a nuclear gene that contains a region homologous to the 59 Tubulin/FtsZ, GTPase superfamily which contains proteins that regulate chromosome 60 segregation in eukaryotes and mitochondrial fission in eukaryotic algae (Kimura and Okano 61 2007). It encodes a soluble cytoplasmic protein that translocates to the mitochondrial outer 62 membrane and promotes normal fusion dynamics (Kimura and Okano 2007; El-Hattab et al. 63 2018; Nasca et al. 2017; Gal et al. 2017). In drosophila knockdown of DML1, the homolog of 64 human MSTO1, leads to defects in chromosome segregation during mitosis (Miklos et al. 1997). 65 In S. cerevisiae, disruption of DML1 causes impaired inheritance of mtDNA and segregation of 66 mitochondria (Gurvitz et al. 2002). Inhibition of MSTO1 in HeLa cells results in nuclear and 67 mitochondrial fragmentation, reduced fusion, and apoptosis, while overexpression results in 68 perinuclear aggregations of mitochondria (Kimura and Okano 2007; Gal et al. 2017). 69 MSTO1 was first associated with human disease in 2017 when Nasca et al. reported on 70 three patients with compound heterozygous variants in MSTO1 presenting with myopathy and 71 cerebellar ataxia (MIM:617675). Functional studies in patient fibroblasts confirmed partially 72 reduced transcript and protein expression as well as fragmentation of the mitochondrial network 73 and decreased mitochondrial fusion (Nasca et al. 2017). To date, a total of 11 patients have 74 been reported in the literature with myopathy and ataxia attributed to pathogenic variants in 75 MSTO1. Consistent phenotypic features observed across patients include onset in the first year 76 of life, severe motor delay, cerebral atrophy on MRI, short stature, myopathic pattern on EMG, 77 and elevated plasma creatine kinase (CK) (Nasca et al. 2017; Iwama et al. 2018; Li, Jin, and Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 78 Wu 2019)(Table 1). Additionally, several patients presented with cognitive deficiencies, skeletal 79 abnormalities, tremors, and retinopathy. 80 Here we present a 30 year old male with phenotypic features consistent with previously 81 reported MSTO1 patients. We report additional phenotypic features seen in our patient including 82 dysphagia and restrictive lung disease which may be the consequence of the associated 83 myopathy. Our patient has a novel partial gene deletion adding to the spectrum of variants 84 associated with MSTO1-associated mitochondrial myopathy. 85 86 RESULTS 87 Clinical Presentation 88 A 30 year old Caucasian male presented with moderate-to-severe proximal and distal 89 muscle weakness and significantly decreased muscle tone. He had congenital hypotonia with 90 poor head control and was diagnosed with “muscular dystrophy of unknown type” at 18 months 91 of age. His gross and fine motor milestones were significantly delayed, including walking at 26 92 months of age and the inability to pedal a bike or run as a child. Learning disability was noted at 93 early childhood. Neurological examination at age 30 was significant for proximal and distal 94 muscle weakness with hypotonia, mild facial weakness with ptosis, diminished muscle bulk, no 95 sensory deficits and preserved muscle reflexes. Gait was wide based and waddling. Swallowing 96 video fluoroscopy revealed mild oropharyngeal dysphagia. Electromyogram (EMG) results were 97 consistent with a longstanding, generalized myopathy, with electrodiagnostic features that would 98 predict fiber splitting, necrosis, inflammation, or vacuolar change. He has persistently elevated 99 CK levels with titers between 1000 and 2000 U/L. Pulmonary function tests showed a chronic 100 restrictive pattern with Forced Vital Capacity (FVC) at 44-49% of predicted leading to a 101 diagnosis of restrictive lung disease (Figure 1A,B). 102 Additional phenotypic features reported in the patient include pectus excavatum that was 103 surgically corrected at age 18, as well as scoliosis characterized by mild reversal of cervical Downloaded from molecularcasestudies.cshlp.org on September 28, 2021 - Published by Cold Spring Harbor Laboratory Press 104 lordosis and a trace gentle convex curvature of the lumbar spine to the right (Figure 1C,D). An 105 echocardiogram was normal. The family history was unremarkable with the exception of a 106 maternal grandmother who died of complication from ALS at age 74 (Figure 2). 107 108 Genomic Analysis 109 Initial genetic testing included a 141 gene panel (Neuromuscular Genetics Panel; Mayo 110 Clinic) and dystrophin deletion/duplication sequencing analysis. None of the variants reported 111 were considered relevant (Table 2). Testing for Pompe’s disease was also negative. 112 Mitochondrial DNA NGS testing was performed through GeneDX, and a homoplasmic variant of 113 uncertain significance (m.8045A>G, p.I154V) was reported in MT-CO2. This variant was also 114 considered not diagnostic as the patient’s unaffected mother was homoplasmic for the same 115 variant. Whole exome sequencing performed through GeneDx reported two potentially clinically 116 relevant variants; a maternally inherited NM_018116.3:c.651C>G, p.F217L missense variant of 117 uncertain significance and a likely pathogenic paternally inherited arr[GRCh37] 118 1q22(155581773_155706887)x1 copy number change (Figure