Identification of a novel MICU1 nonsense variant causes myopathy with extrapyramidal signs in an Iranian consanguineous family

Abstract

Background Ca2+ as a universal second messenger regulates basic biological functions including cell cycle, cell proliferation, cell differentiation, and cell death. Lack of the protein mitochondrial calcium uptake1 (MICU1), which has been regarded as a gatekeeper of Ca ions, leads to the abnormal mitochondrial Ca2+ handling, excessive production of reactive oxygen species (ROS), and increased cell death. Mutations in MICU1 gene causes a very rare neuromuscular disease, myopathy with extrapyramidal signs (MPXPS), due to primary alterations in mitochondrial calcium signaling which demonstrates the key role of mitochondrial Ca2+ uptake. To date, 13 variants have been reported in MICU1 gene in 44 patients presented with the vast spectrum of symptoms. Case presentation Here, we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, gait disturbance, elevated hepatic transaminases, elevated serum creatine kinase (CK), and elevated lactate dehydrogenase (LDH). We identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing (WES) and segregation analysis. Conclusions Our finding along with previous studies provides more evidence on the clinical presentation of the disease caused by pathogenic mutations in MICU1. Finding more variants and expanding the spectrum of the disease increases the diagnostic rate of molecular testing in screening of this kind of diseases and in turn improves the quality of counseling for at risk couples and helps them to minimize the risks of having affected children.

Uncontrolled mitochondrial calcium uptake underlies the pathogenesis of neurodegeneration in MICU1-deficient mice and patients

“…In this study, we showed that neuron-specific homozygous MICU1 deletion in mouse leads to altered neuronal Ca 2+ homeostasis and progressive motor and cognitive dysfunction likely in both males and females. These phenotypes recapitulate those previously reported in patient fibroblasts/lymphoblasts and the symptoms displayed by many MICU1-deficient male and female patients ( 12 – 15 , 62 , 63 ). Heterozygous micu1 neurons and nKO mice have no significant impairments, which is consistent with literature on most individuals with heterozygous MICU1 mutation ( 14 , 15 , 62 ).…”

“…These phenotypes recapitulate those previously reported in patient fibroblasts/lymphoblasts and the symptoms displayed by many MICU1-deficient male and female patients ( 12 – 15 , 62 , 63 ). Heterozygous micu1 neurons and nKO mice have no significant impairments, which is consistent with literature on most individuals with heterozygous MICU1 mutation ( 14 , 15 , 62 ). This is likely because lymphoblasts derived from humans with heterozygous MICU1 mutation ( 15 ), and neurons derived from HT mice (fig.…”

Identification of a novel homozygous synthesis of cytochrome c oxidase 2 variant in siblings with early‐onset axonal Charcot‐Marie‐Tooth disease

“…Mutations in MFN2 (most commonly autosomal dominant) cause Charcot‐Marie‐Tooth disease type 2A (CMT2A), the commonest axonal form of CMT (Pipis et al, 2020). Recessive mutations in the MICU1 gene cause a very rare neuromuscular disease characterized by myopathy with extrapyramidal signs, due to primary alterations in mitochondrial calcium signaling (Bitarafan et al, 2021; Kohlschmidt et al, 2021). However, further functional studies on patient‐derived cells such as fibroblasts or neuronal cells would be needed to study the precise effect of the p.(Gly121Arg)‐ SCO 2 variant on mitochondrial fusion and calcium signaling.…”

Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy – Novel Phenotype of MICU1 Variant c.553C>T

“…The MICU1 protein functions as a calcium uniporter protein and is responsible for delivering calcium ions to the mitochondrial matrix [5]. Pathogenic variants in MICU1 manifest phenotypically with multisystem disease affecting the skeletal muscles (proximal myopathy, ptosis, ophthalmoparesis, dysarthria, scapula alata), the brain (cognitive impairment, mental retardation, attention deficit, depression, insomnia, seizures, extrapyramidal abnormalities (chorea, dystonia, athetosis, tremor, orofacial dyskinesia, tics), ataxia, nystagmus, dysarthria, polymicrogyria, dysmorphic basal ganglia, hypoplastic anterior limbs of internal capsules, cerebellar dysplasia, optic atrophy), the peripheral nerves (axonal neuropathy), the heart (dilated cardiomyopathy), the skeleton (microcephaly, hypertelorism, high arched palate, pes cavus, clinodactyly, hyperlordosis, hyperkyphosis, radioulnar synostosis, low-set ears), the endocrine organs (short stature, hypothyroidism), and the eyes (cataract) [5][6][7][8][9][10][11][12][13][14][15][16]. The most common phenotype is an autosomal recessive, childhood-onset myopathy with proximal muscle weakness with extrapyramidal signs (MPXPS) (OMIM #615673) [15].…”