title: Novel mutations in the inverted formin 2 gene of Chinese families contribute to focal segmental glomerulosclerosis.
abstract: Here, we report a genetic study of an extended family of Chinese ancestry with focal segmental glomerulosclerosis (FSGS), with one of the affected members also concurrently diagnosed with IgA nephropathy (IgAN). By genome-wide linkage analysis and subsequent sequencing, we identified an S85W mutation in the inverted formin 2 (INF2) gene that perfectly cosegregated with the kidney disease phenotype. The entire INF2 coding region was sequenced in 200 healthy controls, 55 families with FSGS, and 34 families with IgAN. This analysis identified a novel insertion, S129_Q130insVRQLS, in another FSGS pedigree. In vitro studies found that α-actinin 4 expression was decreased and INF2 showed perinuclear localization in S85W-transfected podocytes. Phosphorylation of serum response factor, and that its nuclear translation was decreased in S85W podocytes, indicated decreased activation in mutants. Abnormal actin organization was also found in S85W podocytes, while no change of microtubule structure was observed. Co-immunoprecipitation and immunofluorescence found decreased interaction between INF2 and Cdc42 in S85W podocytes. However, all these changes were not found in S129_Q130insVRQLS podocytes. The overall frequency of INF2 mutations was ~3.6% among Chinese familial FSGS, which was considerably lower than that from studies of European FSGS families. Thus, S85W but not the S129_Q130insVRQLS variant leads to podocyte cytoskeletal abnormalities, probably by impaired serum response factor phosphorylation.
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: 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 Pharmacology and Systems Therapeutic, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Evren U
authors.initials: EU
authors.lastname: Azeloglu
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: 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: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
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, People's Republic of China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Ma
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: 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: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhong
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Li
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, People's Republic of China.
authors.forename: Guoyu
authors.initials: G
authors.lastname: Meng
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kiryluk
authors.affiliation: Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: John Cijiang
authors.initials: JC
authors.lastname: He
authors.affiliation: Division of Nephrology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Gharavi
authors.affiliation: Department of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Chen
mesh_terms: D000328:Adult; D000818:Animals; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D048430:Cell Shape; D002478:Cells, Cultured; D002681:China / Q000453:epidemiology; D003599:Cytoskeleton / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D000080865:Formins; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005923:Glomerulosclerosis, Focal Segmental / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D006239:Haplotypes; D040941:Heredity; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010766:Phosphorylation; D050199:Podocytes / Q000378:metabolism; D012307:Risk Factors; D026362:Serum Response Factor / Q000378:metabolism; D014162:Transfection; D055815:Young Adult; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins; C476858:SRF protein, human; D026362:Serum Response Factor; D020764:cdc42 GTP-Binding Protein