PUBLICATION
X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems
- Authors
- Kolvenbach, C.M., Felger, T., Schierbaum, L., Thiffault, I., Pastinen, T., Szczepańska, M., Zaniew, M., Adamczyk, P., Bayat, A., Yilmaz, Ö., Lindenberg, T.T., Thiele, H., Hildebrandt, F., Hinderhofer, K., Moog, U., Hilger, A.C., Sullivan, B., Bartik, L., Gnyś, P., Grote, P., Odermatt, B., Reutter, H.M., Dworschak, G.C.
- ID
- ZDB-PUB-221116-7
- Date
- 2022
- Source
- Journal of Medical Genetics 60(6): 587-596 (Journal)
- Registered Authors
- Hildebrandt, Friedhelm, Odermatt, Benjamin
- Keywords
- congenital, hereditary, and neonatal diseases and abnormalities, digestive system abnormalities, genetic counseling, heart defects, congenital, nervous system malformations
- MeSH Terms
-
- Animals
- Cardiovascular System*
- Central Nervous System
- DNA Copy Number Variations
- Female
- Humans
- Mice
- Morpholinos
- Pregnancy
- Urinary Tract*/abnormalities
- Zebrafish/genetics
- PubMed
- 36379543 Full text @ J. Med. Genet.
Citation
Kolvenbach, C.M., Felger, T., Schierbaum, L., Thiffault, I., Pastinen, T., Szczepańska, M., Zaniew, M., Adamczyk, P., Bayat, A., Yilmaz, Ö., Lindenberg, T.T., Thiele, H., Hildebrandt, F., Hinderhofer, K., Moog, U., Hilger, A.C., Sullivan, B., Bartik, L., Gnyś, P., Grote, P., Odermatt, B., Reutter, H.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. 60(6):587-596.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping