ArticleBrain : a journal of neurology2022
Recurrent de novo mutations in CLDN5 induce an anion-selective blood-brain barrier and alternating hemiplegia.
Article in Brain : a journal of neurology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
20 citing papers in PubMed, 40 citations in OpenAlex.
- Targeting claudins in cancer.Nature reviews. Drug discovery · 2026Review
- Tight junction structure, assembly and (dys)function.Nature reviews. Molecular cell biology · 2026Review
- Review
- Cerebrovascular claudin-5 isoform expression correlates with worsened stroke outcomes following thromboembolic stroke.Fluids and barriers of the CNS · 2026Article
- EHD4 and ASAP2 are critical negative regulators of the claudin-5-based endothelial barrier.The FEBS journal · 2026Article
- Functionalized albumin nanoparticles: A multifunctional platform for enhanced brain drug delivery.Materials today. Bio · 2025Review
- A multi-pore model of the blood-brain barrier tight junction strands recapitulates the permeability features of wild-type and mutant claudin-5.Protein science : a publication of the Protein Society · 2025Article
- Restoring brain barriers: an innovative approach for treating neurological disorders.Fluids and barriers of the CNS · 2025Review
- Clinical Improvement in a Case of Alternating Hemiplegia of Childhood After Cerebral Lymphatic Drainage.International medical case reports journal · 2025Article
- Key Claudins at the Blood-Retina Barriers.Advances in experimental medicine and biology · 2025Review
- Pumilio-1 mediated translational control of claudin-5 at the blood-brain barrier.Fluids and barriers of the CNS · 2024Article
- A loss of function mutation in CLDN25 causing Pelizaeus-Merzbacher-like leukodystrophy.Human molecular genetics · 2024Article
- The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies.International journal of molecular sciences · 2024Review
- Computational Models of Claudin Assembly in Tight Junctions and Strand Properties.International journal of molecular sciences · 2024Review
- Molecular Dynamics Simulations of Claudin-10a and -10b Ion Channels: With Similar Architecture, Different Pore Linings Determine the Opposite Charge Selectivity.International journal of molecular sciences · 2024Article
- Reply: De novo mutations in CLDN5: alternating hemiplegia of childhood or not?Brain : a journal of neurology · 2023Article
- A year in review: brain barriers and brain fluids research in 2022.Fluids and barriers of the CNS · 2023Article
- The CLDN5 gene at the blood-brain barrier in health and disease.Fluids and barriers of the CNS · 2023Review
- The impact of pathogenic and artificial mutations on Claudin-5 selectivity from molecular dynamics simulations.Computational and structural biotechnology journal · 2023Article
- Multiscale modelling of claudin-based assemblies: A magnifying glass for novel structures of biological interfaces.Computational and structural biotechnology journal · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Claudin-5 is the most enriched tight junction protein at the blood-brain barrier. Perturbations in its levels of expression have been observed across numerous neurological and neuropsychiatric conditions; however, pathogenic variants in the coding sequence of the gene have never been reported previously. Here, we report the identification of a novel de novo mutation (c.178G>A) in the CLDN5 gene in two unrelated cases of alternating hemiplegia with microcephaly. This mutation (G60R) lies within the first extracellular loop of claudin-5 and based on protein modelling and sequence alignment, we predicted it would modify claudin-5 to become an anion-selective junctional component as opposed to a purely barrier-forming protein. Generation of stably transfected cell lines expressing wild-type or G60R claudin-5 showed that the tight junctions could still form in the presence of the G60R mutation but that the barrier against small molecules was clearly attenuated and displayed higher Cl- ion permeability and lower Na+ permeability. While this study strongly suggests that CLDN5 associated alternating hemiplegia is a channelopathy, it is also the first study to identify the conversion of the blood-brain barrier to an anion-selective channel mediated by a dominant acting variant in CLDN5.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.