PUBLICATION
The long Filamin-a isoform is required for intestinal development and motility: implications for chronic intestinal pseudo-obstruction
- Authors
- Zada, A., Zhao, Y., Halim, D., Windster, J., van der Linde, H.C., Glodener, J., Overkleeft, S., de Graaf, B.M., Verdijk, R.M., Brooks, A.S., Shepherd, I., Gao, Y., Burns, A.J., Hofstra, R.M.W., Alves, M.M.
- ID
- ZDB-PUB-220819-11
- Date
- 2022
- Source
- Human molecular genetics 32(1): 151-160 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Filamins/genetics
- Filamins/metabolism
- Humans
- Intestinal Pseudo-Obstruction*/genetics
- Intestinal Pseudo-Obstruction*/pathology
- Intestines/pathology
- Protein Isoforms/genetics
- Zebrafish*/genetics
- Zebrafish*/metabolism
- PubMed
- 35981053 Full text @ Hum. Mol. Genet.
Citation
Zada, A., Zhao, Y., Halim, D., Windster, J., van der Linde, H.C., Glodener, J., Overkleeft, S., de Graaf, B.M., Verdijk, R.M., Brooks, A.S., Shepherd, I., Gao, Y., Burns, A.J., Hofstra, R.M.W., Alves, M.M. (2022) The long Filamin-a isoform is required for intestinal development and motility: implications for chronic intestinal pseudo-obstruction. Human molecular genetics. 32(1):151-160.
Abstract
Filamin A (FLNA) is a cytoplasmic actin binding protein, recently shown to be expressed as a long and short isoform. Mutations in FLNA are associated with a wide spectrum of disorders, including an X-linked form of chronic intestinal pseudo-obstruction (CIPO). However, the role of FLNA in intestinal development and function is largely unknown. In this study, we show that FLNA is expressed in the muscle layer of the small intestine from early human fetal stages. Expression of FLNA variants associated with CIPO, blocked expression of the long flna isoform and led to an overall reduction of RNA and protein levels. As a consequence, contractility of human intestinal smooth muscle cells was affected. Lastly, our transgenic zebrafish line showed that the flna long isoform is required for intestinal elongation and peristalsis. Histological analysis revealed structural and architectural changes in the intestinal smooth muscle of homozygous fish, likely triggered by the abnormal expression of intestinal smooth muscle markers. No defect in the localization or numbers of enteric neurons was observed. Taken together, our study demonstrates that the long FLNA isoform contributes to intestinal development and function. Since loss of the long FLNA isoform does not seem to affect the enteric nervous system, it likely results in a myopathic form of CIPO, bringing new insights to disease pathogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping