PMID- 36379543
OWN - NLM
STAT- MEDLINE
DCOM- 20230524
LR  - 20230704
IS  - 1468-6244 (Electronic)
IS  - 0022-2593 (Print)
IS  - 0022-2593 (Linking)
VI  - 60
IP  - 6
DP  - 2023 Jun
TI  - X-linked variations in SHROOM4 are implicated in congenital anomalies of the 
      urinary tract and the anorectal, cardiovascular and central nervous systems.
PG  - 587-596
LID - 10.1136/jmg-2022-108738 [doi]
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.
CI  - (c) Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Kolvenbach, Caroline M
AU  - Kolvenbach CM
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
AD  - Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Felger, Tim
AU  - Felger T
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
FAU - Schierbaum, Luca
AU  - Schierbaum L
AD  - Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
FAU - Thiffault, Isabelle
AU  - Thiffault I
AD  - Genomic Medicine Center, Children's Mercy Hospital, Kansas City, Missouri, USA.
FAU - Pastinen, Tomi
AU  - Pastinen T
AD  - Genomic Medicine Center, Children's Mercy Hospital, Kansas City, Missouri, USA.
FAU - Szczepanska, Maria
AU  - Szczepanska M
AD  - Department of Pediatrics, Faculty of Medical Sciences, Medical University of 
      Silesia in Katowice, Zabrze, Poland.
FAU - Zaniew, Marcin
AU  - Zaniew M
AD  - Department of Pediatrics, University of Zielona Gora, Zielona Gora, Poland.
FAU - Adamczyk, Piotr
AU  - Adamczyk P
AD  - Department of Pediatrics, Faculty of Medical Sciences, Medical University of 
      Silesia, Katowice, Poland.
FAU - Bayat, Allan
AU  - Bayat A
AD  - Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy 
      Centre, Dianalund, Denmark.
AD  - Institute for Regional Health Services, University of Southern Denmark, Odense, 
      Denmark.
FAU - Yilmaz, Oznur
AU  - Yilmaz O
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
FAU - Lindenberg, Tobias T
AU  - Lindenberg TT
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
FAU - Thiele, Holger
AU  - Thiele H
AD  - Cologne Center for Genomics (CCG), Faculty of Medicine, University Hospital 
      Cologne, University of Cologne, Cologne, Germany.
FAU - Hildebrandt, Friedhelm
AU  - Hildebrandt F
AUID- ORCID: 0000-0003-3845-3489
AD  - Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, 
      Boston, Massachusetts, USA.
FAU - Hinderhofer, Katrin
AU  - Hinderhofer K
AD  - Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
FAU - Moog, Ute
AU  - Moog U
AD  - Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
FAU - Hilger, Alina C
AU  - Hilger AC
AD  - Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University 
      of Erlangen-Nurnberg, Erlangen, Germany.
AD  - Research Center On Rare Kidney Diseases (RECORD), University Hospital Erlangen, 
      Erlangen, Germany.
FAU - Sullivan, Bonnie
AU  - Sullivan B
AD  - Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri, 
      USA.
FAU - Bartik, Lauren
AU  - Bartik L
AD  - Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri, 
      USA.
FAU - Gnys, Piotr
AU  - Gnys P
AD  - Medeor Hospital, Department of Genetics, Lodz, Poland.
FAU - Grote, Phillip
AU  - Grote P
AD  - Institute of Cardiovascular Regeneration, Center for Molecular Medicine, Goethe 
      University, Frankfurt am Main, Germany.
AD  - Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 
      Frankfurt am Main, Germany.
FAU - Odermatt, Benjamin
AU  - Odermatt B
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany.
FAU - Reutter, Heiko M
AU  - Reutter HM
AUID- ORCID: 0000-0002-3591-5265
AD  - Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics 
      and Adolescent Medicine, Friedrich-Alexander University of Erlangen-Nurnberg, 
      Erlangen, Germany.
FAU - Dworschak, Gabriel C
AU  - Dworschak GC
AUID- ORCID: 0000-0003-0015-6964
AD  - Institute of Anatomy, Medical Faculty, University of Bonn, Bonn, Germany 
      gabriel.dworschak@uni-bonn.de.
AD  - Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
AD  - Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01 DK068306/DK/NIDDK NIH HHS/United States
GR  - R01 DK076683/DK/NIDDK NIH HHS/United States
GR  - R01 DK088767/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221115
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (Morpholinos)
SB  - IM
MH  - Pregnancy
MH  - Female
MH  - Humans
MH  - Animals
MH  - Mice
MH  - Zebrafish/genetics
MH  - DNA Copy Number Variations
MH  - Morpholinos
MH  - *Urinary Tract/abnormalities
MH  - Central Nervous System
MH  - *Cardiovascular System
PMC - PMC10262053
MID - NIHMS1901205
OTO - NOTNLM
OT  - congenital, hereditary, and neonatal diseases and abnormalities
OT  - digestive system abnormalities
OT  - genetic counseling
OT  - heart defects, congenital
OT  - nervous system malformations
COIS- Competing interests: None declared.
EDAT- 2022/11/16 06:00
MHDA- 2023/05/24 06:42
PMCR- 2023/07/01
CRDT- 2022/11/15 20:43
PHST- 2022/05/30 00:00 [received]
PHST- 2022/10/01 00:00 [accepted]
PHST- 2023/05/24 06:42 [medline]
PHST- 2022/11/16 06:00 [pubmed]
PHST- 2022/11/15 20:43 [entrez]
PHST- 2023/07/01 00:00 [pmc-release]
AID - jmg-2022-108738 [pii]
AID - jmedgenet-2022-108738 [pii]
AID - 10.1136/jmg-2022-108738 [doi]
PST - ppublish
SO  - J Med Genet. 2023 Jun;60(6):587-596. doi: 10.1136/jmg-2022-108738. Epub 2022 Nov 
      15.