X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
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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. / Kolvenbach, Caroline M.; Felger, Tim; Schierbaum, Luca; Thiffault, Isabelle; Pastinen, Tomi; Szczepańska, Maria; Zaniew, Marcin; Adamczyk, Piotr; Bayat, Allan; Yilmaz, Öznur; Lindenberg, Tobias T.; Thiele, Holger; Hildebrandt, Friedhelm; Hinderhofer, Katrin; Moog, Ute; Hilger, Alina C.; Sullivan, Bonnie; Bartik, Lauren; Gnyś, Piotr; Grote, Phillip; Odermatt, Benjamin; Reutter, Heiko M.; Dworschak, Gabriel C.
I: Journal of Medical Genetics, Bind 60, Nr. 6, 01.06.2023, s. 587-596.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
AU - Kolvenbach, Caroline M.
AU - Felger, Tim
AU - Schierbaum, Luca
AU - Thiffault, Isabelle
AU - Pastinen, Tomi
AU - Szczepańska, Maria
AU - Zaniew, Marcin
AU - Adamczyk, Piotr
AU - Bayat, Allan
AU - Yilmaz, Öznur
AU - Lindenberg, Tobias T.
AU - Thiele, Holger
AU - Hildebrandt, Friedhelm
AU - Hinderhofer, Katrin
AU - Moog, Ute
AU - Hilger, Alina C.
AU - Sullivan, Bonnie
AU - Bartik, Lauren
AU - Gnyś, Piotr
AU - Grote, Phillip
AU - Odermatt, Benjamin
AU - Reutter, Heiko M.
AU - Dworschak, Gabriel C.
N1 - Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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.
AB - 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.
KW - congenital, hereditary, and neonatal diseases and abnormalities
KW - digestive system abnormalities
KW - genetic counseling
KW - heart defects, congenital
KW - nervous system malformations
U2 - 10.1136/jmg-2022-108738
DO - 10.1136/jmg-2022-108738
M3 - Journal article
C2 - 36379543
AN - SCOPUS:85144375834
VL - 60
SP - 587
EP - 596
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 6
ER -
ID: 389676721