Liang-Liang Fan1,2,3, Lv Liu4, Fang-Mei Luo2,3, Ran Du2,3, Chen-Yu Wang2,3, Yi Dong2,3, Ji-Shi Liu1. 1. Department of Nephrology, The Third Xiangya Hospital of Central South University, Changsha, China. 2. Department of Cell Biology, The School of Life Sciences, Central South University, Changsha, China. 3. Hunan Key Laboratory of Animal for Human Disease, School of Life Sciences, Central South University, Changsha, China. 4. Department of Respiratory Medicine, Diagnosis and Treatment Center of Respiratory Disease, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Rajasree Menon; Edgar A Otto; Paul Hoover; Sean Eddy; Laura Mariani; Bradley Godfrey; Celine C Berthier; Felix Eichinger; Lalita Subramanian; Jennifer Harder; Wenjun Ju; Viji Nair; Maria Larkina; Abhijit S Naik; Jinghui Luo; Sanjay Jain; Rachel Sealfon; Olga Troyanskaya; Nir Hacohen; Jeffrey B Hodgin; Matthias Kretzler; Kidney Precision Medicine Project Kpmp Journal: JCI Insight Date: 2020-03-26
Authors: T Mochizuki; H H Lemmink; M Mariyama; C Antignac; M C Gubler; Y Pirson; C Verellen-Dumoulin; B Chan; C H Schröder; H J Smeets Journal: Nat Genet Date: 1994-09 Impact factor: 38.330
Authors: José María García-Aznar; Luis De la Higuera; Lara Besada Cerecedo; Nerea Paz Gandiaga; Ana Isabel Vega; Gema Fernández-Fresnedo; Domingo González-Lamuño Journal: J Clin Med Date: 2022-08-19 Impact factor: 4.964