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COL4A3 mutations cause focal segmental glomerulosclerosis Free
Jingyuan Xie1,†, Xiaoxi Wu2,†, Hong Ren1, Weiming Wang1, Zhaohui Wang1, Xiaoxia Pan1, Xu Hao1, Jun Tong1, Jun Ma1, Zhibin Ye3, Guoyu Meng4, Yufei Zhu2, Krzysztof Kiryluk5, Xiangyin Kong2, Landian Hu2,*, and Nan Chen1,*
1Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
2State Key Laboratory for Medical Genomics, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai, China
3Nephrology Department, Huadong Hospital Affiliated to Fudan University, Shanghai, China
4State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
5Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA *Correspondence to:Nan Chen, E-mail: cnrj100@126.com; Landian Hu, E-mail: ldhu@sibs.ac.cn
J Mol Cell Biol, Volume 6, Issue 6, December 2014, Pages 498-505  https://doi.org/10.1093/jmcb/mju040
Keyword: FSGS, mutation, COL4A3, COL4A4

Focal segmental glomerulosclerosis (FSGS) is a histologically identifiable glomerular injury often leading to proteinuria and renal failure. To identify its causal genes, whole-exome sequencing and Sanger sequencing were performed on a large Chinese cohort that comprised 40 FSGS families, 50 sporadic FSGS patients, 9 independent autosomal recessive Alport's syndrome (ARAS) patients, and 190 ethnically matched healthy controls. Patients with extrarenal manifestations, indicating systemic diseases or other known hereditary renal diseases, were excluded. Heterozygous COL4A3 mutations were identified in five (12.5%) FSGS families and one (2%) sporadic FSGS patient. All identified mutations disrupted highly conserved protein sequences and none of them was found in either public databases or the 190 healthy controls. Of the FSGS patients with heterozygous COL4A3 mutations, segmental thinning of the glomerular base membrane (GBM) was only detected in the patient with electronic microscopy examination results available. Five ARAS patients (55.6%) had homozygous or compound-heterozygous mutations in COL4A3 or COL4A4. Serious changes in the GBM, hearing loss, and ocular abnormalities were found in 100%, 80%, and 40% of the ARAS patients, respectively. Overall, a new subgroup of FSGS patients resulting from heterozygous COL4A3 mutations was identified. The mutations are relatively frequent in families diagnosed with inherited forms of FSGS. Thus, we suggest screening for COL4A3 mutations in familial FSGS patients.