ADCK4相关肾小球病8例分析
Clinical and genetic characters of 8 Chinese children with ADCK4-associated glomerulopathy
目的 分析8例含aarF域激酶4(aarF domain containing kinase 4,ADCK4)相关肾小球病患儿临床特征及基因突变的特点,以提高对该疾病的认识.方法 应用二代测序技术对69例表现为激素耐药肾病综合征(steroid resistant nephritic syndrome,SRNS)的原发性肾病综合征患儿或原因不明的持续性蛋白尿患儿进行肾脏疾病相关单基因的基因测序,并进行相关的生物信息学分析,用Sanger法对有意义的致病位点进行验证,并对其父母也做相关位点的验证;整理并分析ADCK4基因突变患儿的临床资料(起病年龄、临床表现、肾脏病理等).结果 69例患儿中有8例携带ADCK4基因突变,其中6例纯合突变(3例为c.748G>C纯合突变,3例为c.737G>A纯合突变),2例复合杂合突变(1例为c.748G>C和c.737G>A复合杂合突变,1例为c.551A>G和c.737G>A复合杂合突变),这3个突变位点均为未见相关疾病报道的错义突变,经PolyPhen 2、SIFT和Mutation Taster预测均为致病性突变,所编码的氨基酸均较为保守;8例患儿平均起病年龄6岁7个月(2岁至11岁8个月),其中4例表现为SRNS,4例表现为蛋白尿,均无肾外症状,肾脏病理以局灶性节段性肾小球硬化(FSGS)为主,3例患儿在起病时即已进入终末期肾病(ESRD),1例于起病5年后进入ESRD,l例起病2年后进入ESRD,7例患儿给予过免疫抑制治疗,其中6例均无明显效果,1例对激素和他克莫司获得部分疗效,目前4例患儿行腹膜透析,1例于起病7个月后肾移植,基因诊断明确后,均予以大剂量辅酶Q10口服治疗,部分患儿获得一定疗效.结论 ADCK4基因缺陷在表现为SRNS的原发性肾病综合征患儿和不明原因持续蛋白尿的患儿中并不少见,其起病年龄相对较大,肾外表型较少,病理上多表现为FSGS,部分患儿起病隐匿,仅有蛋白尿,临床不易早期发现.激素及免疫抑制剂对患儿的治疗效果较差,辅酶Q10补充治疗对于部分患儿有一定效果.新发现的3个ADCK4基因的错义突变丰富了ADCK4致病基因突变谱系,且其中c.748G>C和c.737G>A或为中国汉族人群的致病热点突变.
更多Objective To investigate the clinical and genetic character of Chinese children with the aarF domain containing kinase 4 (ADCK4)-associated glomerulopathy.Methods Applying next generation sequencing to detect possible gene mutation(renal disease associated monogene was pooled as one panel) in 69 children with steroid-resistant nephrotic syndrome (SRNS) or persistent proteinuria of unknown origin.Sanger sequencing was used to confirm the significant mutations found in the children and to validate these mutation sites in their patients.Using online software (PolyPhen2,SIFT,Mutation Taster) to predict whether the detected missense mutations were disease causing or not.Collecting and analyzing clinical data of children with ADCK4-associated glomerulopathy,which included onset age,clinical manifestation,and renal pathology.Results The ADCK4 gene mutation was detected in 8 children with a positive rate of 11.6% (8 out of 69),among which 3 patients carried homozygous c.748G>C mutation,3 patients carried homologous c.737G>A mutation,1 patient carried compound heterozygous mutation(c.748G>C and c.737G>A),and 1 patient carried compound heterologous mutation(c.551A>G and c.737G>A).Collectively,there were only 3 mutation sites found in total 8 patients,in which the mutation sites of c.748G>C and c.737G>A had high detection frequency in these 8 patients.These 3 mutation sites were all missense mutation which were predicted to be disease causing by online software and not reported before.The average onset age was 6.5 years (2 years11.75 years).Four patients presented with SRNS and the other 4 presented with persistent proteinuria.All 8 patients had no extrarenal manifestation,renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in most patients,among which 3 cases had gone to end-stage renal disease (ESRD) at disease onset,and 2 cases progressed to ESRD 2 and 5 years after onset respectively.Seven patients had received glucocorticoid and/or immunosuppressive drug while only one patient getting partial response.All 8 patients were treated with large amount of coenzyme Q10 (15 mg· kg-1· d-1) after definite diagnosis of ADCK4 mutation-some patients had acquired encouraging curative effect.Conclusions ADCK4-associated glomerulopathy is not rare especially in the children with SRNS.The onset age is relatively old and the extrarenal manifestation is less common.FSGS is a main pathology type.Patients usually have no response to immunosuppressive therapy,but may benefit from addition of large amount of coenzyme Q10.Some patients may only manifest with insidious proteinuria,causing the early diagnosis to be difficult,which deserves more attention.Three new missense mutations expand disease causing mutation repertoire of ADCK4 gene,among which the two sites of c.748G>C and c.737G>A may be mutation hotspot of ADCK4-associated glomerulopathy in Chinese population,and need further study.
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