A rat model of a focal mosaic expression of PCDH19 replicates human brain developmental abnormalities and behaviours

Cwetsch, Andrzej; Ziogas, Ilias; Narducci, Roberto; Savardi, Annalisa; Bolla, Maria; Pinto, Bruno; Perlini, Laura E.; Bassani, Silvia; Passafaro, Maria; Cancedda, Laura

doi:10.1093/braincomms/fcac091

Cited by 5 publications

(4 citation statements)

References 62 publications

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“…As c.2760T>A was a novel variant located at the exon 5 of the PCDH19 gene influencing the structure of the CM1 domain of PCDH19 protein, the phenotype differences between our pedigree and previous cases were probably related to this variant requiring further experiments to verify this hypothesis. From the function perspective, PCDH19 functions were also diverse such as its adhesive or signal transduction properties with potential influence on structural layering on hippocampus layering ( 41 , 42 ). A complete PCDH19 ectodomain model was put forward recently, which can assist in the evaluation of epilepsy-related variants and protein interaction sites ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Zhou

Ouyang²,

Ji³

et al. 2023

Front. Neurol.

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ObjectiveAlbeit the gene of PCDH19-FE was ascertained, the correlation of gene mutation, PCDH19 protein structure, and phenotype heterogeneity remained obscure. This study aimed to report a five-generation pedigree of seven female patients of PCDH19-FE and tried to explore whether two variants were correlated with PCDH19 protein structure and function alteration, and PCDH19-FE phenotype.MethodsWe analyzed the clinical data and genetic variants of a PCDH19-FE pedigree, to explore the phenotype heterogeneity of PCDH19-FE and underlying mechanisms. In addition to the clinical information of family members, next-generation sequencing was adopted to detect the variant sites of probands with validation by sanger sequencing. And the sanger sequencing was conducted in other patients in this pedigree. The biological conservation analysis and population polymorphism analysis of variants were also performed subsequently. The structure alteration of mutated PCDH19 protein was predicted by AlphaFold2.ResultsBased on a five-generation pedigree of PCDH19-FE, missense variants of c.695A>G and c.2760T>A in the PCDH19 gene were found in the heterozygous proband (V:1), which resulted in the change of amino acid 232 from Asn to Ser (p.Asn232Ser) and amino acid 920 from Asp to Glu (p.Asp920Glu) influencing PCDH19 function. The other six females in the pedigree (II:6, II:8, IV:3, IV:4, IV:5, IV:11) exhibited different clinical phenotypes but shared the same variant. Two males with the same variant have no clinical manifestations (III:3, III:10). The biological conservation analysis and population polymorphism analysis demonstrated the highly conservative characteristics of these two variants. AlphaFold2 predicted that the variant, p.Asp920Glu, led to the disappearance of the hydrogen bond between Asp at position 920 and His at position 919. Furthermore, the hydrogen bond between Asp920 and His919 also disappeared when the Asn amino acid mutated to Ser at position 232.ConclusionA strong genotype-phenotype heterogeneity was observed among female patients with the same genotype in our PCDH19-FE pedigree. And two missense variants, c.695A > G and c.2760T>A in the PCDH19 gene, have been identified in our pedigree. The c.2760T>A variant was a novel variant site probably related to the PCDH19-FE.

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Section: Discussionmentioning

confidence: 99%

Genetic variants and phenotype analysis in a five-generation Chinese pedigree with PCDH19 female-limited epilepsy

Zhou

Ouyang²,

Ji³

et al. 2023

Front. Neurol.

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“…Studies in animal models show that PCDH19 expression is organized in relatively large patches [ 11 , 12 ] and that the loss of PCDH19 affects neuronal migration [ 31 ]. Given this background, it is not surprising that some DEE9 patients exhibit cortical dysplasia and folding abnormalities [ 11 , 32 , 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Perturbation of Cortical Excitability in a Conditional Model of PCDH19 Disorder

Lamers

Landi

Mezzena

et al. 2022

Cells

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PCDH19 epilepsy (DEE9) is an X-linked syndrome associated with cognitive and behavioral disturbances. Since heterozygous females are affected, while mutant males are spared, it is likely that DEE9 pathogenesis is related to disturbed cell-to-cell communication associated with mosaicism. However, the effects of mosaic PCDH19 expression on cortical networks are unknown. We mimicked the pathology of DEE9 by introducing a patch of mosaic protein expression in one hemisphere of the cortex of conditional PCDH19 knockout mice one day after birth. In the contralateral area, PCDH19 expression was unaffected, thus providing an internal control. In this model, we characterized the physiology of the disrupted network using local field recordings and two photon Ca2+ imaging in urethane anesthetized mice. We found transient episodes of hyperexcitability in the form of brief hypersynchronous spikes or bursts of field potential oscillations in the 9–25 Hz range. Furthermore, we observed a strong disruption of slow wave activity, a crucial component of NREM sleep. This phenotype was present also when PCDH19 loss occurred in adult mice, demonstrating that PCDH19 exerts a function on cortical circuitry outside of early development. Our results indicate that a focal mosaic mutation of PCDH19 disrupts cortical networks and broaden our understanding of DEE9.

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“… 24 , 25 , 26 Consistent with this, multiple animal models of epilepsy have been developed to exhibit hyperthermia-evoked seizures, triggered by elevation of environmental temperature. 27 , 28 , 29 , 30 , 31 Combining hyperthermia-evoked seizures with optogenetic or chemogenetic techniques offers a naturalistic, acute seizure method to dissect circuit mechanisms of ictogenesis. 1 In this protocol, we describe how to manipulate hyperthermia-evoked seizure temperature threshold using optogenetics or chemogenetics in vivo .…”

Section: Before You Beginmentioning

confidence: 99%