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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

SUBMITTER: Connaughton DM

PROVIDER: S-EPMC7536580 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Connaughton Dervla M DM Dai Rufeng R Owen Danielle J DJ Marquez Jonathan J Mann Nina N Graham-Paquin Adda L AL Nakayama Makiko M Coyaud Etienne E Laurent Estelle M N EMN St-Germain Jonathan R JR Blok Lot Snijders LS Vino Arianna A Klämbt Verena V Deutsch Konstantin K Wu Chen-Han Wilfred CW Kolvenbach Caroline M CM Kause Franziska F Ottlewski Isabel I Schneider Ronen R Kitzler Thomas M TM Majmundar Amar J AJ Buerger Florian F Onuchic-Whitford Ana C AC Youying Mao M Kolb Amy A Salmanullah Daanya D Chen Evan E van der Ven Amelie T AT Rao Jia J Ityel Hadas H Seltzsam Steve S Rieke Johanna M JM Chen Jing J Vivante Asaf A Hwang Daw-Yang DY Kohl Stefan S Dworschak Gabriel C GC Hermle Tobias T Alders Mariëlle M Bartolomaeus Tobias T Bauer Stuart B SB Baum Michelle A MA Brilstra Eva H EH Challman Thomas D TD Zyskind Jacob J Costin Carrie E CE Dipple Katrina M KM Duijkers Floor A FA Ferguson Marcia M Fitzpatrick David R DR Fick Roger R Glass Ian A IA Hulick Peter J PJ Kline Antonie D AD Krey Ilona I Kumar Selvin S Lu Weining W Marco Elysa J EJ Wentzensen Ingrid M IM Mefford Heather C HC Platzer Konrad K Povolotskaya Inna S IS Savatt Juliann M JM Shcherbakova Natalia V NV Senguttuvan Prabha P Squire Audrey E AE Stein Deborah R DR Thiffault Isabelle I Voinova Victoria Y VY Somers Michael J G MJG Ferguson Michael A MA Traum Avram Z AZ Daouk Ghaleb H GH Daga Ankana A Rodig Nancy M NM Terhal Paulien A PA van Binsbergen Ellen E Eid Loai A LA Tasic Velibor V Rasouly Hila Milo HM Lim Tze Y TY Ahram Dina F DF Gharavi Ali G AG Reutter Heiko M HM Rehm Heidi L HL MacArthur Daniel G DG Lek Monkol M Laricchia Kristen M KM Lifton Richard P RP Xu Hong H Mane Shrikant M SM Sanna-Cherchi Simone S Sharrocks Andrew D AD Raught Brian B Fisher Simon E SE Bouchard Maxime M Khokha Mustafa K MK Shril Shirlee S Hildebrandt Friedhelm F

American journal of human genetics 20200904 4

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through colla ...[more]

PMID: 32891193

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Project description:BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

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Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

Publications

Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.

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