Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Shahid Hemmat Highway, Tehran, Iran.
Department of medical genetics, Ali-Asghar Children's Hospital, Zafar St., Shahid Modarres Highway, Tehran, Iran.
BMC Med Genet. 2020 Apr 15;21(1):77. doi: 10.1186/s12881-020-01016-y.
Myopathy with extrapyramidal signs (MPXPS) is an autosomal recessive mitochondrial disorder which is caused by mutation in mitochondrial calcium uptake 1 (MICU1) gene located on chromosome 10q22.1. Next Generation Sequencing (NGS) technology is the most effective method for identification of pathogenic variants with the ability to overcome some limitations which Sanger sequencing may encountered. There are few reports on this rare disease around the world and here in this study we first revealed genetic identification of two affected individuals in an Iranian family with a novel mutation.
The proband was a 5-year-old girl from consanguenous parents. She was first clinically suspicious of affected with limb-girdle muscular dystrophy (LGMD). Muscle biopsy studies and autozygosity mapping, using four short tandem repeat (STR) markers linked to 6 genes of the most prevalent forms of LGMD, ruled out calpainopathy, dysferlinopathy, and sarcoglycanopathis. DNA sample of the proband was sent for NGS. Whole exome sequencing (WES) revealed a novel mutation c.1295delA in exon 13 of MICU1 gene. This homozygous deletion creates a frameshift and a premature stop codon downstream of canonical EF4 calcium binding motif of MICU1. According to the American College of Medical Genetics and Genomics (ACMG) guidline for sequence interpretation, this variant was a pathogenic one. Sanger sequencing in all family members confirmed the results of the WES.
This study was the first report of MPXPS in Iranian population which also revealed a novel mutation in the MICU1 gene.
伴外显运动障碍的肌病（MPXPS）是一种常染色体隐性遗传的线粒体疾病，由位于 10q22.1 染色体上的线粒体钙摄取 1（MICU1）基因突变引起。下一代测序（NGS）技术是识别致病变异的最有效方法，能够克服桑格测序可能遇到的一些限制。这种罕见疾病在世界范围内仅有少数报道，本研究首次揭示了一个伊朗家系中两个受影响个体的遗传鉴定，该家系存在一个新的突变。
先证者为一对近亲所生的 5 岁女孩，最初临床怀疑患有肢带型肌营养不良症（LGMD）。肌肉活检研究和使用与最常见形式的 LGMD 相关的 6 个基因的 4 个短串联重复（STR）标记的自交系作图排除了钙蛋白酶病、肌营养不良蛋白病和肌聚糖病。将先证者的 DNA 样本送检进行 NGS。全外显子组测序（WES）显示 MICU1 基因第 13 外显子的 c.1295delA 新型突变。这种纯合缺失导致 MICU1 的经典 EF4 钙结合基序下游产生移码和过早终止密码子。根据美国医学遗传学与基因组学学院（ACMG）序列解读指南，该变体是一种致病性变体。对所有家庭成员进行的 Sanger 测序证实了 WES 的结果。
本研究首次报道了伊朗人群中的 MPXPS，并揭示了 MICU1 基因的一个新突变。
