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

IF 2.4 Q1 PEDIATRICS
Fatemeh Bitarafan, Mehrnoosh Khodaeian, Elham Amjadi Sardehaei, Fatemeh Zahra Darvishi, Navid Almadani, Yalda Nilipour, Masoud Garshasbi
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引用次数: 7

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.

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鉴定一种新的MICU1无义变异导致伊朗近亲家族锥体外系症状的肌病。
背景:Ca2+作为一种通用的第二信使,调节细胞周期、细胞增殖、细胞分化和细胞死亡等基本生物学功能。线粒体钙摄取蛋白MICU1被认为是钙离子的看门人,缺乏MICU1会导致线粒体Ca2+处理异常,活性氧(ROS)过量产生,以及细胞死亡增加。MICU1基因突变导致一种非常罕见的神经肌肉疾病,即锥体外系体征(MPXPS)的肌病,这是由于线粒体钙信号的原发性改变,这表明了线粒体Ca2+摄取的关键作用。迄今为止,在44名表现出广泛症状的患者中,已报告了13种MICU1基因变异。病例介绍:在这里,我们报告了一名44岁的伊朗患者,表现为学习障碍,肌肉无力,易疲劳,肌腱反射减少,共济失调,步态障碍,肝转氨酶升高,血清肌酸激酶(CK)升高,乳酸脱氢酶(LDH)升高。我们发现了一个新的无义变异c.385C>T;通过全外显子组测序(WES)和分离分析鉴定MICU1基因p.(R129*)。结论:我们的发现与先前的研究一起为MICU1致病性突变引起的疾病的临床表现提供了更多证据。发现更多的变异和扩大疾病的范围,提高了分子检测在筛查这类疾病中的诊断率,进而提高了对有风险夫妇的咨询质量,并帮助他们尽量减少生育受影响儿童的风险。
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