WITHDRAWN: Identification of a Novel MICU1 Nonsense Variant Causes Myopathy with Extrapyramidal Signs in an Iranian Consanguineous Family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 (NM_006077.3) 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 6 variants have been reported in MICU1 gene in approximately 21 pedigrees.Case presentation: here we report a 44-year-old Iranian patient presented with learning disability, muscle weakness, easy fatigability, reduced tendon reflexes, ataxia, elevated hepatic transaminase, elevated serum creatine phosphokinase and gait disturbance. We Identified a novel nonsense variant c.385C>T; p.(R129*) in MICU1 gene by whole exome sequencing 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

“…These phenotypes recapitulate those previously reported in patient fibroblasts/lymphoblasts and the symptoms displayed by many MICU1deficient 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 de rived from humans with heterozygous MICU1 mutation (15), and neurons derived from HT mice (fig.…”