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X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems

dc.contributor.authorKolvenbach, Caroline
dc.contributor.authorFelger, Tim
dc.contributor.authorSchierbaum, Luca
dc.contributor.authorThiffault, Isabelle
dc.contributor.authorPastinen, Tomi
dc.contributor.authorSzczepańska, Maria
dc.contributor.authorZaniew, Marcin
dc.contributor.authorAdamczyk, Piotr
dc.contributor.authorBayat, Allan
dc.contributor.authorYilmaz, Öznur
dc.contributor.authorLindenberg, Tobias
dc.contributor.authorThiele, Holger
dc.contributor.authorHildebrandt, Friedhelm
dc.contributor.authorHinderhofer, Katrin
dc.contributor.authorMoog, Ute
dc.contributor.authorHilger, Alina
dc.contributor.authorSullivan, Bonnie
dc.contributor.authorBartik, Lauren
dc.contributor.authorGnyś, Piotr
dc.contributor.authorGrote, Phillip
dc.contributor.authorOdermatt, Benjamin
dc.contributor.authorReutter, Heiko
dc.contributor.authorDworschak, Gabriel
dc.date.accessioned2023-05-02T07:47:45Z
dc.date.available2023-05-02T07:47:45Z
dc.date.issued15.11.2022
dc.identifier.urihttps://hdl.handle.net/20.500.11811/10814
dc.description.abstractBackground: 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.en
dc.format.extent10
dc.language.isoeng
dc.rightsNamensnennung-Nicht kommerziell 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectcongenital, hereditary, and neonatal diseases and abnormalities
dc.subjectdigestive system abnormalities
dc.subjectgenetic counseling
dc.subjectheart defects, congenital
dc.subjectnervous system malformations
dc.subject.ddc610 Medizin, Gesundheit
dc.titleX-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
dc.typeWissenschaftlicher Artikel
dc.publisher.nameBMJ
dc.rights.accessRightsopenAccess
dcterms.bibliographicCitation.volume2022
dcterms.bibliographicCitation.pagestart1
dcterms.bibliographicCitation.pageend10
dc.relation.doihttps://doi.org/10.1136/jmg-2022-108738
dcterms.bibliographicCitation.journaltitleJournal of Medical Genetics
ulbbn.pubtypeZweitveröffentlichung
dc.versionpublishedVersion
ulbbn.sponsorship.oaUnifundOA-Förderung Universität Bonn


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