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

Caroline M Kolvenbach, Tim Felger, Luca Schierbaum, Isabelle Thiffault, Tomi Pastinen, Maria Szczepańska, Marcin Zaniew, Piotr Adamczyk, Allan Bayat, Öznur Yilmaz, Tobias T Lindenberg, Holger Thiele, Friedhelm Hildebrandt, Katrin Hinderhofer, Ute Moog, Alina C Hilger, Bonnie Sullivan, Lauren Bartik, Piotr Gnyś, Phillip GroteBenjamin Odermatt, Heiko M Reutter, Gabriel C Dworschak*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

17 Downloads (Pure)

Abstract

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.

Original languageEnglish
JournalJournal of Medical Genetics
Volume60
Issue number6
Pages (from-to)587-596
ISSN0022-2593
DOIs
Publication statusPublished - 22. May 2023

Bibliographical note

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Fingerprint

Dive into the research topics of 'X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems'. Together they form a unique fingerprint.

Cite this