PUBLICATION
Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications
- Authors
- Deshwar, A.R., Cytrynbaum, C., Murthy, H., Zon, J., Chitayat, D., Volpatti, J., Newbury-Ecob, R., Ellard, S., Lango Allen, H., Yu, E.P., Noche, R., Walker, S., Scherer, S.W., Mahida, S., Elitt, C.M., Nicolas, G., Goldenberg, A., Saugier-Veber, P., Lecoquierre, F., Dabaj, I., Meddaugh, H., Marble, M., Keppler-Noreuil, K.M., Drayson, L., Barañano, K.W., Chassevent, A., Agre, K., Létard, P., Bilan, F., Le Guyader, G., Laquerrière, A., Ramsey, K., Henderson, L., Brady, L., Tarnopolsky, M., Bainbridge, M., Friedman, J., Capri, Y., Athayde, L., Kok, F., Gurgel-Giannetti, J., Ramos, L.L.P., Blaser, S., Dowling, J.J., Weksberg, R.
- ID
- ZDB-PUB-221209-6
- Date
- 2022
- Source
- Brain : a journal of neurology 146(6): 2285-2297 (Journal)
- Registered Authors
- Murthy, Harsha, Volpatti, Jonathan
- Keywords
- CLDN5, blood brain barrier, brain calcifications
- MeSH Terms
-
- Animals
- Blood-Brain Barrier/metabolism
- Claudin-5/genetics
- Claudin-5/metabolism
- Humans
- Microcephaly*/genetics
- Seizures/genetics
- Syndrome
- Zebrafish/metabolism
- PubMed
- 36477332 Full text @ Brain
Citation
Deshwar, A.R., Cytrynbaum, C., Murthy, H., Zon, J., Chitayat, D., Volpatti, J., Newbury-Ecob, R., Ellard, S., Lango Allen, H., Yu, E.P., Noche, R., Walker, S., Scherer, S.W., Mahida, S., Elitt, C.M., Nicolas, G., Goldenberg, A., Saugier-Veber, P., Lecoquierre, F., Dabaj, I., Meddaugh, H., Marble, M., Keppler-Noreuil, K.M., Drayson, L., Barañano, K.W., Chassevent, A., Agre, K., Létard, P., Bilan, F., Le Guyader, G., Laquerrière, A., Ramsey, K., Henderson, L., Brady, L., Tarnopolsky, M., Bainbridge, M., Friedman, J., Capri, Y., Athayde, L., Kok, F., Gurgel-Giannetti, J., Ramos, L.L.P., Blaser, S., Dowling, J.J., Weksberg, R. (2022) Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications. Brain : a journal of neurology. 146(6):2285-2297.
Abstract
The blood brain barrier ensures central nervous system homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the BBB. We have identified de novo heterozygous missense variants in CLDN5 in fifteen unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modeled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients likely result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood brain barrier and impaired neuronal function.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping