title: COL4A3 mutations cause focal segmental glomerulosclerosis.
abstract: 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.
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Xie
authors.affiliation: State 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.
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Ren
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tong
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Nephrology Department, Huadong Hospital Affiliated to Fudan University, Shanghai, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Ye
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Meng
authors.affiliation: State 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.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kiryluk
authors.affiliation: State 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.
authors.forename: Xiangyin
authors.initials: X
authors.lastname: Kong
authors.affiliation: State 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 cnrj100@126.com ldhu@sibs.ac.cn.
authors.forename: Landian
authors.initials: L
authors.lastname: Hu
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China cnrj100@126.com ldhu@sibs.ac.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
mesh_terms: D000328:Adult; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D024141:Collagen Type IV / Q000235:genetics* / Q000378:metabolism; D005190:Family; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: D001324:Autoantigens; C466620:COL4A4 protein, human; D024141:Collagen Type IV; C057112:type IV collagen alpha3 chain
keywords: COL4A3; COL4A4; FSGS; mutation