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Congenital enteropathy caused by ezrin deficiency
Georg F Vogel1,2, Katharina M C Klee2, Arzu Meltem Demir3
1Department of Paediatrics I, Medical University of Innsbruck, Anichstrasse 35, Innsbruck, 6020, Austria.
Human Genetics
|March 26, 2025
Summary
Complete ezrin (EZR) deficiency in a human infant caused severe intestinal defects and failure to thrive. This study confirms ezrin
Area of Science:
- Cell Biology
- Genetics
- Human Physiology
Background:
- Ezrin (EZR) is crucial for epithelial polarity, connecting membrane proteins to the actin cytoskeleton.
- Ezrin deficiency in mice leads to failure to thrive and mortality.
- No homozygous EZR loss-of-function variants had been previously reported in humans.
Purpose of the Study:
- To investigate the role of ezrin in human intestinal epithelia.
- To characterize the consequences of complete ezrin deficiency in a human infant.
- To analyze structural and functional changes in intestinal cells lacking ezrin.
Main Methods:
- Exome sequencing identified a homozygous EZR loss-of-function variant in an infant.
- Analysis of EZR transcript in a heterozygous carrier revealed nonsense-mediated mRNA decay.
- A Caco-2 EZR knockout cell line was generated for cellular analysis using microscopy.
Main Results:
- A homozygous EZR loss-of-function variant (c.356dup) was identified in an infant with intractable diarrhea and failure to thrive.
- The EZR variant segregated with disease in the family and triggered nonsense-mediated mRNA decay.
- EZR knockout cells showed disorganization of the terminal web, microvillus abnormalities, and mislocalization of ezrin-interacting proteins.
Conclusions:
- This study documents the first case of complete ezrin deficiency in humans.
- Ezrin is essential and non-redundant for maintaining human intestinal epithelial structure and function.
- Complete ezrin deficiency leads to severe intestinal pathology and is likely lethal without intervention.
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