Yiting Wang1, Junlin Zhang1, Yingwang Zhao1, Shanshan Wang1, Jie Zhang2, Qianqian Han1, Rui Zhang1, Ruikun Guo1, Hanyu Li1, Li Li1, Tingli Wang1, Xi Tang1, Changzheng He3, Geer Teng4, Weiyue Gu5, Fang Liu6. 1. Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China. 2. Key Laboratory of Transplant Engineering and Immunology, Ministry of Health, Regenerative Medicine Research Center, Chengdu, China. 3. Business School and. 4. Institute of Social Development and Western China Development Studies, Sichuan University, Chengdu, Sichuan, China; and. 5. Joy Orient Translational Medicine Research Center Co., Ltd., Beijing, China. 6. Division of Nephrology, West China Hospital of Sichuan University, Chengdu, Sichuan, China; liufangfh@163.com.
Abstract
BACKGROUND AND OBJECTIVES: Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. RESULTS: HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. CONCLUSIONS: The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.
BACKGROUND AND OBJECTIVES: Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. RESULTS:HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. CONCLUSIONS: The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.
Authors: H U Irgens; J Molnes; B B Johansson; M Ringdal; T Skrivarhaug; D E Undlien; O Søvik; G Joner; A Molven; P R Njølstad Journal: Diabetologia Date: 2013-04-27 Impact factor: 10.122
Authors: Y Ohta; Y Tanizawa; H Inoue; T Hosaka; K Ueda; A Matsutani; V P Repunte; M Yamada; Y Kurachi; J Bryan; L Aguilar-Bryan; M A Permutt; Y Oka Journal: Diabetes Date: 1998-03 Impact factor: 9.461
Authors: Thijs W Cohen Tervaert; Antien L Mooyaart; Kerstin Amann; Arthur H Cohen; H Terence Cook; Cinthia B Drachenberg; Franco Ferrario; Agnes B Fogo; Mark Haas; Emile de Heer; Kensuke Joh; Laure H Noël; Jai Radhakrishnan; Surya V Seshan; Ingeborg M Bajema; Jan A Bruijn Journal: J Am Soc Nephrol Date: 2010-02-18 Impact factor: 10.121
Authors: Merlin C Thomas; Michael Brownlee; Katalin Susztak; Kumar Sharma; Karin A M Jandeleit-Dahm; Sophia Zoungas; Peter Rossing; Per-Henrik Groop; Mark E Cooper Journal: Nat Rev Dis Primers Date: 2015-07-30 Impact factor: 52.329
Authors: Maggie Shepherd; Beverley Shields; Suzanne Hammersley; Michelle Hudson; Timothy J McDonald; Kevin Colclough; Richard A Oram; Bridget Knight; Christopher Hyde; Julian Cox; Katherine Mallam; Christopher Moudiotis; Rebecca Smith; Barbara Fraser; Simon Robertson; Stephen Greene; Sian Ellard; Ewan R Pearson; Andrew T Hattersley Journal: Diabetes Care Date: 2016-06-06 Impact factor: 19.112
Authors: W Fendler; M Borowiec; A Baranowska-Jazwiecka; A Szadkowska; E Skala-Zamorowska; G Deja; P Jarosz-Chobot; I Techmanska; J Bautembach-Minkowska; M Mysliwiec; A Zmyslowska; I Pietrzak; M T Malecki; W Mlynarski Journal: Diabetologia Date: 2012-07-11 Impact factor: 10.122
Authors: Erica L-W Majumder; Elizabeth M Billings; H Paul Benton; Richard L Martin; Amelia Palermo; Carlos Guijas; Markus M Rinschen; Xavier Domingo-Almenara; J Rafael Montenegro-Burke; Bradley A Tagtow; Robert S Plumb; Gary Siuzdak Journal: Nat Protoc Date: 2021-01-22 Impact factor: 13.491
Authors: Prasad Devarajan; Glenn M Chertow; Katalin Susztak; Adeera Levin; Rajiv Agarwal; Peter Stenvinkel; Arlene B Chapman; Bradley A Warady Journal: Kidney Med Date: 2022-02-11