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

TitleGeneration of Monogenic Candidate Genes for Human Nephrotic Syndrome Using 3 Independent Approaches.
Publication TypeJournal Article
Year of Publication2021
AuthorsKlämbt, V, Mao, Y, Schneider, R, Buerger, F, Shamseldin, H, Onuchic-Whitford, AC, Deutsch, K, Kitzler, TM, Nakayama, M, Majmundar, AJ, Mann, N, Hugo, H, Widmeier, E, Tan, W, Rehm, HL, Mane, S, Lifton, RP, Alkuraya, FS, Shril, S, Hildebrandt, F
JournalKidney Int Rep
Date Published2021 Feb

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 . We show that loss-of-function of 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 as a novel potential monogenic cause of NS.

Alternate JournalKidney Int Rep
PubMed ID33615071
PubMed Central IDPMC7879125
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States
F32 DK122766 / DK / NIDDK NIH HHS / United States