Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, China.
Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China.
Mol Genet Genomic Med. 2020 Dec;8(12):e1545. doi: 10.1002/mgg3.1545. Epub 2020 Nov 7.
Focal segmental glomerulosclerosis (FSGS), as the frequent primary glomerular diseases in adults, accounts for symptomless proteinuria or nephrotic syndrome with or without renal insufficiency. As the crucial lesion of chronic kidney disease (CKD), accumulating evidence from recent studies show that mutations in Collagen-related genes may be responsible for FSGS. The aim of this study was to identify the genetic lesion of a Chinese family with FSGS and CKD.
In this study, we recruited a Han-Chinese family with unexplained high serum creatinine, hematuria, and proteinuria. Further renal biopsy and renal pathology indicated the diagnosis of FSGS in the proband. Whole-exome sequencing and Sanger sequencing were employed to explore the pathogenic mutation of this family.
A novel heterozygous mutation (NM_000092 c.2030G>A, p.G677D) of the collagen type IV alpha-4 gene (COL4A4) was detected. Co-segregation analysis revealed that the novel mutation was carried by all the five affected individuals and absent in other healthy members as well as in our 200 local control cohorts. Bioinformatics predication indicated that this novel mutation was pathogenic and may disrupt the structure and function of type IV collagen. Simultaneously, this variant is located in an evolutionarily conserved site of COL4A4 protein.
Here, we identified a novel mutation of COL4A4 in a family with FSGS and CKD. Our study expanded the variants spectrum of the COL4A4 gene and contributed to the genetic counseling and prenatal genetic diagnosis of the family. In addition, we also recommended the new classification of collagen IV nephropathies, which may be a benefit to the diagnosis, target drug treatment, and management of patients with COL4A3/COL4A4 mutations.
局灶节段性肾小球硬化症（FSGS）是成人中常见的原发性肾小球疾病，表现为无症状性蛋白尿或肾病综合征，伴有或不伴有肾功能不全。作为慢性肾脏病（CKD）的关键病变，最近的研究证据表明，胶原相关基因的突变可能与 FSGS 有关。本研究旨在鉴定一个 FSGS 和 CKD 中国家族的遗传病变。
本研究纳入了一个汉族家族，该家族成员血清肌酐、血尿和蛋白尿升高，原因不明。进一步的肾脏活检和肾脏病理学检查提示先证者为 FSGS。采用全外显子组测序和 Sanger 测序技术探讨该家族的致病突变。
发现了胶原类型 IV alpha-4 基因（COL4A4）的一个新的杂合突变（NM_000092 c.2030G>A，p.G677D）。共分离分析表明，该新突变存在于所有 5 名受影响个体中，而不存在于其他健康个体以及我们的 200 名当地对照人群中。生物信息学预测表明，该新突变是致病性的，可能破坏 IV 型胶原的结构和功能。同时，该变体位于 COL4A4 蛋白的进化保守位点。
本研究在一个 FSGS 和 CKD 家族中鉴定出 COL4A4 的一个新突变。我们的研究扩展了 COL4A4 基因的变异谱，为该家族的遗传咨询和产前遗传诊断提供了依据。此外，我们还建议了一种新的胶原 IV 肾病分类，这可能有助于对 COL4A3/COL4A4 突变患者的诊断、靶向药物治疗和管理。
