PDF(Pubmed)
Abstract：
UNASSIGNED: Combined Oxidative Phosphorylation Deficiency 23 (COXPD23) is a rare mitochondrial disease caused by mutations in the GTPBP3 gene. The rare incidence of the disease and the high clinical heterogeneity pose challenges in making a precise diagnosis. Investigations into the rare COXPD23 patients are of pathophysiological and etiological value. In this study, we investigated the genotype-phenotype relationship in a COXPD23 patient from a Manchu family, with GTPBP3 mutations.
UNASSIGNED: Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay.
UNASSIGNED: The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons.
UNASSIGNED: The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23.
UNASSIGNED: Routine physical examinations, laboratory assays and imaging analyses were performed. The metabolic profiles of amino acids in blood, acylcarnitine in blood and organic acids in urine were used to determine the presence of inherited metabolic diseases. Genetic variations in the family were investigated using whole-exome sequencing and Sanger sequencing. Splicing disruption by a mutation was predicted and verified using a minigene assay.
UNASSIGNED: The patient presented with severe lactic acidosis, neurological symptoms, multiple symmetrical lesions in the brain and serious mitochondrial energy metabolism disturbances. The c.689A > C (p.Q230P) and c.809-1_809delinsA compound heterozygous mutations were detected in GTPBP3. The novel c.809-1_809delinsA mutation was located at the splicing site of exon 7 and intron 6 and multiple tools predicted that it would disrupt the normal splicing. The minigene assay proved that the novel mutation resulted in two aberrant transcripts that created premature termination codons.
UNASSIGNED: The clinical manifestations, brain imaging change, mitochondrial metabolism disturbances and the detection and validation of the GTPBP3 mutations expand the profile of COXPD23 and the pathogenic mutation spectrum. Our study improves the understanding of the pathophysiology and etiology of COXPD23.
摘要：
■联合氧化磷酸化缺陷23（COXPD23）是一种由GTPBP3基因突变引起的罕见线粒体疾病。该疾病的罕见发病率和高临床异质性对做出精确诊断提出了挑战。对罕见的COXPD23患者的研究具有病理生理和病因学价值。在这项研究中,我们调查了来自满族家庭的COXPD23患者的基因型-表型关系，与GTPBP3突变。
■常规体检，进行了实验室检测和影像学分析.血液中氨基酸的代谢谱，血液中的酰基肉碱和尿液中的有机酸用于确定遗传代谢疾病的存在。使用全外显子组测序和Sanger测序研究了该家族的遗传变异。使用小基因测定预测和验证由突变引起的剪接破坏。
■患者出现严重乳酸性酸中毒，神经症状,大脑中的多个对称病变和严重的线粒体能量代谢障碍。c.689A>C（p。在GTPBP3中检测到Q230P）和c.809-1_809delinsA复合杂合突变。新的c.809-1_809delinsA突变位于外显子7和内含子6的剪接位点，多种工具预测它会破坏正常的剪接。小基因测定证明，新的突变导致两个产生过早终止密码子的异常转录本。
■临床表现，脑成像改变，线粒体代谢紊乱以及GTPBP3突变的检测和验证扩展了COXPD23的概况和致病突变谱.我们的研究提高了对COXPD23的病理生理学和病因学的理解。
■常规体检，进行了实验室检测和影像学分析.血液中氨基酸的代谢谱，血液中的酰基肉碱和尿液中的有机酸用于确定遗传代谢疾病的存在。使用全外显子组测序和Sanger测序研究了该家族的遗传变异。使用小基因测定预测和验证由突变引起的剪接破坏。
■患者出现严重乳酸性酸中毒，神经症状,大脑中的多个对称病变和严重的线粒体能量代谢障碍。c.689A>C（p。在GTPBP3中检测到Q230P）和c.809-1_809delinsA复合杂合突变。新的c.809-1_809delinsA突变位于外显子7和内含子6的剪接位点，多种工具预测它会破坏正常的剪接。小基因测定证明，新的突变导致两个产生过早终止密码子的异常转录本。
■临床表现，脑成像改变，线粒体代谢紊乱以及GTPBP3突变的检测和验证扩展了COXPD23的概况和致病突变谱.我们的研究提高了对COXPD23的病理生理学和病因学的理解。
