Generation of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches

Kidney International Reports

Fowzan S. Alkuraya¹  Ronen Schneider²  Thomas M. Kitzler³  Friedhelm Hildebrandt⁴  Ana C. Onuchic-Whitford⁵  Shirlee Shril⁶  Weizhen Tan⁷  Heidi L. Rehm⁷  Verena Klämbt⁷  Eugen Widmeier⁷  Konstantin Deutsch⁷  Makiko Nakayama⁷  Amar J. Majmundar⁷  Youying Mao⁷  Florian Buerger⁷  Hanan Shamseldin⁷  Shrikant Mane⁷  Nina Mann⁷  Hannah Hugo⁷  Richard P. Lifton⁸ 

[1] Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;Nephrology Department, Shanghai Children's Medical Center, Shanghai Jiaotong University, Shanghai, China;Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, Connecticut, USA;Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA;Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;Program in Medical and Population Genetics, Broad Center for Mendelian Genetics, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts;

关键词: pediatric nephrology;    proteinuria;    recessive disease;    whole-exome sequencing;   

DOI  :  

来源: DOAJ

【 摘 要 】

Introduction: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of chronic kidney disease during childhood. Identification of 63 monogenic human genes has delineated 12 distinct pathogenic pathways. Methods: Here, we generated 2 independent sets of nephrotic syndrome (NS) candidate genes to augment the discovery of additional monogenic causes based on whole-exome sequencing (WES) data from 1382 families with NS. Results: We first identified 63 known monogenic causes of NS in mice from public databases and scientific publications, and 12 of these genes overlapped with the 63 known human monogenic SRNS genes. Second, we used a set of 64 genes that are regulated by the transcription factor Wilms tumor 1 (WT1), which causes SRNS if mutated. Thirteen of these WT1-regulated genes overlapped with human or murine NS genes. Finally, we overlapped these lists of murine and WT1 candidate genes with our list of 120 candidate genes generated from WES in 1382 NS families, to identify novel candidate genes for monogenic human SRNS. Using this approach, we identified 7 overlapping genes, of which 3 genes were shared by all datasets, including SYNPO. We show that loss-of-function of SYNPO leads to decreased CDC42 activity and reduced podocyte migration rate, both of which are rescued by overexpression of wild-type complementary DNA (cDNA), but not by cDNA representing the patient mutation. Conclusion: Thus, we identified 3 novel candidate genes for human SRNS using 3 independent, nonoverlapping hypotheses, and generated functional evidence for SYNPO as a novel potential monogenic cause of NS.

【 授权许可】

Unknown