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目的分析1个常染色体显性局灶节段肾小球硬化(AD-FSGS)家系的临床特征及可能的致病基因。方法调查1个中国AD-FSGS家系,收集临床资料,绘制家系图谱,并对家系中所有成员进行尿液筛查,并留取其外周血,对其中尿液筛查异常的2个家庭7名成员进行ACTN4、TRPC6和INF2基因所有外显子,以及WT1基因外显子8和9直接测序。生物信息学初步分析突变位点对蛋白结构和功能的影响。结果该家系共有4代,27名成员,现有成员23名。发病者5例,女性3例,男性2例,平均发病年龄26.9岁。临床资料分析显示,该家系临床特点符合AD-FSGS诊断。7名成员中未发现ACTN4、TRPC6基因所有外显子和WT1基因外显子8、9有致病性突变,其中5例发病者INF2基因外显子8均有纯合缺失突变,缺失的碱基为CCCCACCCCCAC(c.1249delCCCCACCCCCAC,p.T420_P423del),缺失在外显子8第274～285位点,该位点突变既往未见报道。c.1249delCCCCACCCCCAC位于INF2表达分子invertedformin重要的Diaphanous抑制结构域(DID)编码区。结论 INF2基因外显子8上的杂合缺失突变可能是该家系AD-FSGS患者的致病原因,c.1249delCCCCACCCCCAC是引起AD-FSGS的一种新型突变。
Objective To analyze the clinical features and possible pathogenic genes in an autosomal dominant focal segmental glomerulosclerosis (AD-FSGS) pedigree. Methods One Chinese AD-FSGS pedigree was investigated. The clinical data were collected and the pedigree was drawn. All the members of the pedigree were screened for urine and their peripheral blood was collected. Seven of the two families with abnormal urine screening were collected. Members performed direct sequencing of all exons of the ACTN4, TRPC6 and INF2 genes, and exons 8 and 9 of the WT1 gene. Bioinformatics analysis of the impact of mutation sites on protein structure and function. Results The pedigree has a total of 4 generations, 27 members and 23 current members. Incidence in 5 cases, 3 females, 2 males, the average age of onset 26.9 years old. Clinical data analysis showed that the pedigree clinical features consistent with AD-FSGS diagnosis. Seven members of ACTN4, TRPC6 gene all exons and WT1 gene exons 8,9 have pathogenic mutations, of which 5 cases of INF2 gene exon 8 homozygous deletion mutation, deletion of the base The base is CCCCACCCCCAC (c.1249delCCCCACCCCCAC, p.T420_P423del), which is deleted from the 274th to the 285th positions of exon 8. The mutation of this site has not been reported in the past. c.1249delCCCCACCCCCAC located in the INF2 expression invertedformin important Diaphanous inhibitory domain (DID) coding region. Conclusion The heterozygous deletion mutation in exon 8 of INF2 gene may be the causative agent of AD-FSGS in this pedigree. C.1249delCCCCACCCCCAC is a novel mutation that causes AD-FSGS.