Kolvenbach, Caroline M., Felger, Tim, Schierbaum, Luca, Thiffault, Isabelle, Pastinen, Tomi, Szczepanska, Maria ORCID: 0000-0002-6772-1983, Zaniew, Marcin, Adamczyk, Piotr ORCID: 0000-0001-9557-221X, Bayat, Allan ORCID: 0000-0003-4986-8006, Yilmaz, Oeznur, Lindenberg, Tobias T., Thiele, Holger, Hildebrandt, Friedhelm, Hinderhofer, Katrin, Moog, Ute, Hilger, Alina C., Sullivan, Bonnie, Bartik, Lauren, Gnys, Piotr, Grote, Phillip, Odermatt, Benjamin, Reutter, Heiko M. and Dworschak, Gabriel C. . X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems. J. Med. Genet.. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

BackgroundSHROOM4 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. MethodsHere, 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. ResultsIn 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. ConclusionThe 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Kolvenbach, Caroline M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Felger, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schierbaum, LucaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiffault, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pastinen, TomiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szczepanska, MariaUNSPECIFIEDorcid.org/0000-0002-6772-1983UNSPECIFIED
Zaniew, MarcinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adamczyk, PiotrUNSPECIFIEDorcid.org/0000-0001-9557-221XUNSPECIFIED
Bayat, AllanUNSPECIFIEDorcid.org/0000-0003-4986-8006UNSPECIFIED
Yilmaz, OeznurUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lindenberg, Tobias T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hildebrandt, FriedhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hinderhofer, KatrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moog, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilger, Alina C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sullivan, BonnieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartik, LaurenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gnys, PiotrUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grote, PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odermatt, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reutter, Heiko M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dworschak, Gabriel C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-694722
DOI: 10.1136/jmg-2022-108738
Journal or Publication Title: J. Med. Genet.
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MENTAL-RETARDATION; GENE; CHROMOSOME; IDENTIFICATION; PHENOTYPE; HYBRIDIZATION; LOCALIZATION; MUTATIONS; KIAA1202; DISEASEMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69472

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