X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Background SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system. Methods Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development. Results In this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino. Conclusion The identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Journal of Medical Genetics |
| Vol/bind | 60 |
| Udgave nummer | 6 |
| Sider (fra-til) | 587-596 |
| Antal sider | 10 |
| ISSN | 0022-2593 |
| DOI | |
| Status | Udgivet - 1 jun. 2023 |
| Eksternt udgivet | Ja |
Bibliografisk note
Funding Information:
CMK was funded by the SciMed BONFOR stipends (O-149.0120 and O-167.0021), by the German Research Foundation (DFG, KO 6579/2-1) (708037-809683, 499462148) and supported by the Biomedical Education Program (BMEP). IT and TP work was made possible by the generous gifts to Children’s Mercy Research Institute and Genomic Answers for Kids program at Children’s Mercy Kansas City. Data are available online ( https://github.com/ChildrensMercyResearchInstitute/GA4K ). FH was supported by the National Institutes of Health NIH (DK068306). ACH was funded by the BONFOR grant (O-149.0123) and partially funded by the Else Kröner-Fresenius-Stiftung and the Eva Luise und Horst Köhler Stiftung (project number 2019_KollegSE.04). We are grateful for a German Research Foundation (DFG) equipment grant (INST 1172/37-1 FUGG) to BO for a multiphoton microscope set-up. HR was funded by the German Research Foundation (DFG, RE 1723/4-1) and by the Else-Kröner-Fresenius-Stiftung (EKFS, 2014_A14). G.CD was funded by the BONFOR grant (O-120.0001).
Funding Information:
We thank the participating families and physicians for their contribution. Zebrafish work was supported by Bonn medical faculty zebrafish core facility. Tg(wt1b:GFP) zebrafish was provided by Christoph Englert. This study makes use of data generated by the DECIPHER community. A full list of centres which contributed to the generation of the data is available online ( https://deciphergenomics.org/about/stats ) and via email from contact@deciphergenomics.org. Funding for the DECIPHER project was provided by Wellcome.
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