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目的总结2例线粒体相关肾病患儿临床特征及基因突变的特点,提高对该病的认识。方法收集2例线粒体相关肾病患儿的病史特点、肾脏病理、相关实验室检查和家族史等资料。采用外显子捕获的方法对4 000种人类单基因病的相关致病基因进行高通量测序,包括线粒体DNA A3243G等37个基因和ADCK4等13个参与辅酶Q10生物合成的基因,利用生物信息学对测序结果进行分析,用Sanger法对高通量测序结果进行验证,并在家系中进行突变分析。并进行相关文献复习。结果 2例患儿男女各1例。女性患儿11.7岁起病,主要临床表现为蛋白尿和肾功能异常,无肾外症状,肾脏病理为局灶节段性肾小球硬化(FSGS),检测到NPHS1基因已报道的p.E447K和p.G601A杂合突变,ADCK4基因纯合p.D209H错义突变,为新发现的突变。家系突变分析发现,NPHS1基因p.E447K和p.G601A杂合突变均来自父亲,其哥哥也有相同的基因型,其母亲不携带该2个突变;患儿父母和哥哥分别携带p.D209H杂合突变。男性患儿出生后起病,多个系统受累,表现为精神、运动发育落后,心脏和大血管多发畸形,肾病综合征。检测到COQ6基因的纯合p.R360W错义突变,为新发现的突变。家系突变分析显示,患儿父母分别携带杂合p.R360W错义突变。ADCK4基因p.D209H错义突变和COQ6基因p.R360W错义突变经在线软件Poly Phen和SIFT预测为有害性突变,经多物种蛋白序列比对,2个突变位点均具有保守性。结论 2例患儿肾脏表型分别由辅酶Q10合成基因ADCK4和COQ6突变引起的线粒体相关肾病。新发现p.D209H和p.R360W突变分别丰富了ADCK4和COQ6基因突变谱。
Objective To summarize the clinical features and gene mutation in 2 children with mitochondria-associated nephropathy and to improve their understanding of the disease. Methods Two cases of children with mitochondria-related nephrology were collected, including their history, renal pathology, laboratory tests and family history. Exon capture method was used to high-throughput sequencing of 4,000 genes related to human monogenic disease, including 37 genes such as mitochondrial DNA A3243G and 13 genes involved in the biosynthesis of coenzyme Q10, such as ADCK4. Bioinformatics The results of sequencing were analyzed, the high-throughput sequencing results were validated by the Sanger method, and the mutation analysis was performed in the pedigree. And review the relevant literature. Results There were 1 male and 1 female in 2 cases. Female children onset at 11.7 years old, the main clinical manifestations of proteinuria and renal dysfunction, no symptoms of extrarenal renal pathology as focal segmental glomerulosclerosis (FSGS), NPHS1 gene has been detected p.E447K And p.G601A heterozygous mutation, ADCK4 gene homozygous p.D209H missense mutation, as a newly discovered mutation. Family mutation analysis found that NPHS1 gene p.E447K and p.G601A heterozygous mutations are from his father, his brother also has the same genotype, the mother does not carry the two mutations; children and their parents were carrying p.D209H heterozygous mutation. Male children born after onset, multiple system involvement, manifested as mental, athletic development, multiple heart and large blood vessel malformations, nephrotic syndrome. The homozygous p.R360W missense mutation of the COQ6 gene was detected as a newly discovered mutation. Family mutation analysis showed that children with parents were carrying heterozygous p.R360W missense mutation. The p.D209H missense mutation of the ADCK4 gene and the p.R360W missense mutation of the COQ6 gene were predicted to be detrimental mutations by on-line software Poly Phen and SIFT. The alignment of the two mutation sites was conservative by protein sequence alignment of multiple species. Conclusions The kidney phenotypes of two children were caused by mitochondria-associated nephropathy caused by the mutations of ADCK4 and COQ6 of coenzyme Q10. Newly found p.D209H and p.R360W mutations enrich the ADCK4 and COQ6 gene mutation profiles, respectively.