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

Kolvenbach CM, Felger T, Schierbaum L, Thiffault I, Pastinen T, Szczepanska M, Zaniew M, Adamczyk P, Bayat A, Yilmaz O, Lindenberg TT, Thiele H, Hildebrandt F, Hinderhofer K, Moog U, Hilger AC, Sullivan B, Bartik L, Gnys P, Grote P, Odermatt B, Reutter HM, Dworschak GC (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Medical Genetics BMJ Publishing Group

DOI: 10.1136/jmg-2022-108738

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.

Authors with CRIS profile

Heiko Martin Reutter Professur für Neonatologie

Involved external institutions

Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Children's Mercy Hospital US United States (USA) (US) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) Filadelfia DK Denmark (DK) Universität zu Köln DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE) Medeor Szpital Wielospecjalistyczny w Łodzi PL Poland (PL) Harvard University US United States (USA) (US) Medical University of Silesia in Katowice / Śląski Uniwersytet Medyczny w Katowicach (SUM) PL Poland (PL) University of Zielona Góra / Uniwersytet Zielonogórski PL Poland (PL)

How to cite

APA:

Kolvenbach, C.M., Felger, T., Schierbaum, L., Thiffault, I., Pastinen, T., Szczepanska, M.,... Dworschak, G.C. (2022). X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems. Journal of Medical Genetics. https://doi.org/10.1136/jmg-2022-108738

MLA:

Kolvenbach, Caroline M., et al. "X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems." Journal of Medical Genetics (2022).

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