A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients.
A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients.
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DOI：
10.1007/8904_2018_107
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发表时间：
2019-01-01
期刊：
影响因子：
--
通讯作者：
Ben-Omran, Tawfeg
中科院分区：
文献类型：
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作者：
Musa, Sara;Eyaid, Wafaa;Ben-Omran, Tawfeg
MICU1编码线粒体单向转运体的Ca2+感应调节亚基，线粒体单向转运体是细胞器内膜内的选择性钙通道。Ca2+进入线粒体有助于缓冲胞质Ca2+瞬变，并激活细胞器内的ATP产生。先前已报道来自9个家族的17名儿童发生MICU1突变，这些儿童患有肌无力、疲劳、正常乳酸和肌酸激酶持续升高，以及包括进行性锥体外系体征、学习障碍、眼球震颤和白内障在内的可变特征。在这项研究中，我们报告了另外13例来自中东近亲家族的MICU1隐性突变患者的临床特征。在这些患者中，12/13例患者为新创始突变c.553C> T（p.Q185 *）纯合子，该突变预计会导致MICU 1功能完全丧失，而1例患者为该突变和外显子9和10基因内重复的复合杂合子。创始者突变在ExAC数据库中以1：60，000的次要等位基因频率发生，但在中东个体中约为1：500。所有13例患者均表现为发育迟缓、学习障碍、肌无力和易疲劳、发育不良以及我们列表中的其他可变特征。与以前的病例一致，所有这些患者的血清肌酸激酶持续升高，乳酸水平正常，但他们也表现出转氨酶升高。我们的工作有助于更好地定义MICU1缺陷的临床后遗症。此外，我们的工作表明，可能需要对中东患者的MICU1创始人突变进行有针对性的分析。
MICU1 encodes a Ca2+ sensing, regulatory subunit of the mitochondrial uniporter, a selective calcium channel within the organelle's inner membrane. Ca2+ entry into mitochondria helps to buffer cytosolic Ca2+ transients and also activates ATP production within the organelle. Mutations in MICU1 have previously been reported in 17 children from nine families with muscle weakness, fatigue, normal lactate, and persistently elevated creatine kinase, as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts. In this study, we report the clinical features of an additional 13 patients from consanguineous Middle Eastern families with recessive mutations in MICU1. Of these patients, 12/13 are homozygous for a novel founder mutation c.553C>T (p.Q185*) that is predicted to lead to a complete loss of function of MICU1, while one patient is compound heterozygous for this mutation and an intragenic duplication of exons 9 and 10. The founder mutation occurs with a minor allele frequency of 1:60,000 in the ExAC database, but in ~1:500 individual in the Middle East. All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive, as well as additional variable features we tabulate. Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes. Our work helps to better define the clinical sequelae of MICU1 deficiency. Furthermore, our work suggests that targeted analysis of the MICU1 founder mutation in Middle Eastern patients may be warranted.