【摘要】 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。更多还原

【Abstract】 Objective To summarize and review the clinical data of two children with mitochondrial nephropathy so as to improve it’ s knowledge. Methods Clinical data of two cases with mitochondrial nephropathy were summarized, including clinical manifestations,laboratory findings,renal pathological changes and family investigation. This study used next generation sequencing to screen 4 000 genes,including the 40 genes known to be associated with mitochondrial disease. Significant variants detected by next generation sequencing were confirmed by conventional Sanger sequencing and segregation analysis was performed using parental DNA samples. Results In two cases,one is a boy,the other is a girl. Age onset of the girl was 11. 7 years. She presented with proteinuria,renal dysfunction, no extrarenal symptoms and focal segmental glomerulosclerosis( FSGS) in renal biopsy.Heterozygous p. E447 and p. G601 A mutations in NPHS1 and homozygous p. D209 H mutation in ADCK4 gene were detected and confirmed by next-generation sequencing and conventional Sanger sequencing,respectively. Family analysis showed that the girl had same genotype in NPHS1 gene with her father and sibling,and her homozygous p. D209 H mutation in ADCK4 gene was from parents. The boy presented with congenital heart disease and mental retardation after birth,and nephrotic syndrome in few months later. Homozygous p. R360 W mutation in COQ6 gene was identified and confirmed by next-generation sequencing and Sanger sequencing,respectively. Family analysis showed that homozygous p. R360 W mutation in COQ6 gene inherited from his parents.Missense p. D209 H and p. R360 W mutations were damaging by prediction online Poly Phen and SIFT software. Protein multiple alignment showed site in p. D209 H and p. R360 W mutations both were conservative. Conclusion Two cases with renal phenotype were caused by casual mutations in ADCK4 and COQ6 gene,respectively. These two cases could be diagnosed as mitochondrial nephropathy. One case with mutation in ADCK4 gene presented with proteinuria,renal dysfunction,no extrarenal symptoms and FSGS in renal biopsy. The other with mutation in COQ6 gene had nephrotic syndrome,except congenital heart disease and mental retardation.更多还原