A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling
CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. Hundreds of pathogenic variants have been described, associated with a significant phenotypic heterogeneity observed among patients. To date, different knockout mouse models have bee...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-11-01
|
| Series: | Heliyon |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844024161968 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846166965340602368 |
|---|---|
| author | C. Quadalti M. Sannia N.E. Humphreys V.A. Baldassarro A. Gurgone M. Ascolani L. Zanella L. Giardino C.T. Gross S. Croci I. Meloni M. Giustetto A. Renieri L. Lorenzini L. Calzà |
| author_facet | C. Quadalti M. Sannia N.E. Humphreys V.A. Baldassarro A. Gurgone M. Ascolani L. Zanella L. Giardino C.T. Gross S. Croci I. Meloni M. Giustetto A. Renieri L. Lorenzini L. Calzà |
| author_sort | C. Quadalti |
| collection | DOAJ |
| description | CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. Hundreds of pathogenic variants have been described, associated with a significant phenotypic heterogeneity observed among patients. To date, different knockout mouse models have been generated. Here we present a new knockin CDKL5 mouse model carrying a humanized, well-characterized nonsense variant (c.1090G > T; p.E364X) described in the C-terminal domain of the CDKL5 protein in a female patient with a milder phenotype. Both male and female Cdkl5E364X mice were analyzed. The novel Cdkl5E364X mouse showed altered neurological and motor neuron maturation, hyperactivity, defective coordination and impaired memory and cognition. Gene expression analysis highlighted an unexpected reduction of Cdkl5 expression in Cdkl5E364X mice brain tissues, with a significant increase in overall neuron-specific gene expression and an area-dependent alteration of astrocyte- and oligodendrocyte-specific transcripts. Moreover, our results showed that the loss of CDKL5 protein had the most significant impact on the cerebellum and hippocampus, compared to other analyzed tissues. A targeted analysis to study synaptic plasticity in cerebellum and hippocampus showed reduced Gabra1 and Gabra5 expression levels in females, whereas Gabra1 expression was increased in males, suggesting an opposite, sex-dependent regulation of the GABA receptor expression already described in humans. In conclusion, the novel Cdkl5E364X mouse model is characterized by robust neurological and neurobehavioral alterations, associated with a molecular profile related to synaptic function indicative of a cerebellar GABAergic hypofunction, pointing to Gabra1 and Gabra5 as novel druggable target candidates for CDD. |
| format | Article |
| id | doaj-art-56ddabb048be41ef958959507b9fd035 |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj-art-56ddabb048be41ef958959507b9fd0352024-11-15T06:14:32ZengElsevierHeliyon2405-84402024-11-011021e40165A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profilingC. Quadalti0M. Sannia1N.E. Humphreys2V.A. Baldassarro3A. Gurgone4M. Ascolani5L. Zanella6L. Giardino7C.T. Gross8S. Croci9I. Meloni10M. Giustetto11A. Renieri12L. Lorenzini13L. Calzà14Department of Pharmacy and Biotechnology, University of Bologna, Bologna, ItalyIRET Foundation, 40064 Ozzano Emilia (Bologna), ItalyEpigenetics & Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Rome, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, ItalyDepartment of Neuroscience “Rita Levi-Montalcini”, University of Turin, 10125 Turin, ItalyEpigenetics & Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Rome, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, ItalyEpigenetics & Neurobiology Unit, European Molecular Biology Laboratory (EMBL), Rome, ItalyMedical Genetics, University of Siena, 53100 Siena, ItalyMedical Genetics, University of Siena, 53100 Siena, ItalyDepartment of Neuroscience “Rita Levi-Montalcini”, University of Turin, 10125 Turin, ItalyMedical Genetics, University of Siena, 53100 Siena, Italy; Medical Genetics Department, Siena University Hospital, 53100 Siena, ItalyDepartment of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, ItalyDepartment of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy; Corresponding author. Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy Via Tolara di Sopra 41/E 40064 Ozzano Emilia Bologna Italy.CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental syndrome caused by mutations in the X-linked CDKL5 gene. Hundreds of pathogenic variants have been described, associated with a significant phenotypic heterogeneity observed among patients. To date, different knockout mouse models have been generated. Here we present a new knockin CDKL5 mouse model carrying a humanized, well-characterized nonsense variant (c.1090G > T; p.E364X) described in the C-terminal domain of the CDKL5 protein in a female patient with a milder phenotype. Both male and female Cdkl5E364X mice were analyzed. The novel Cdkl5E364X mouse showed altered neurological and motor neuron maturation, hyperactivity, defective coordination and impaired memory and cognition. Gene expression analysis highlighted an unexpected reduction of Cdkl5 expression in Cdkl5E364X mice brain tissues, with a significant increase in overall neuron-specific gene expression and an area-dependent alteration of astrocyte- and oligodendrocyte-specific transcripts. Moreover, our results showed that the loss of CDKL5 protein had the most significant impact on the cerebellum and hippocampus, compared to other analyzed tissues. A targeted analysis to study synaptic plasticity in cerebellum and hippocampus showed reduced Gabra1 and Gabra5 expression levels in females, whereas Gabra1 expression was increased in males, suggesting an opposite, sex-dependent regulation of the GABA receptor expression already described in humans. In conclusion, the novel Cdkl5E364X mouse model is characterized by robust neurological and neurobehavioral alterations, associated with a molecular profile related to synaptic function indicative of a cerebellar GABAergic hypofunction, pointing to Gabra1 and Gabra5 as novel druggable target candidates for CDD.http://www.sciencedirect.com/science/article/pii/S2405844024161968CDKL5CDDCRISPR/Cas9 knockinGABAGabra1Gabra5 |
| spellingShingle | C. Quadalti M. Sannia N.E. Humphreys V.A. Baldassarro A. Gurgone M. Ascolani L. Zanella L. Giardino C.T. Gross S. Croci I. Meloni M. Giustetto A. Renieri L. Lorenzini L. Calzà A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling Heliyon CDKL5 CDD CRISPR/Cas9 knockin GABA Gabra1 Gabra5 |
| title | A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling |
| title_full | A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling |
| title_fullStr | A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling |
| title_full_unstemmed | A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling |
| title_short | A new knockin mouse carrying the E364X patient mutation for CDKL5 deficiency disorder: neurological, behavioral and molecular profiling |
| title_sort | new knockin mouse carrying the e364x patient mutation for cdkl5 deficiency disorder neurological behavioral and molecular profiling |
| topic | CDKL5 CDD CRISPR/Cas9 knockin GABA Gabra1 Gabra5 |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024161968 |
| work_keys_str_mv | AT cquadalti anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT msannia anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT nehumphreys anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT vabaldassarro anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT agurgone anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT mascolani anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lzanella anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lgiardino anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT ctgross anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT scroci anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT imeloni anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT mgiustetto anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT arenieri anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT llorenzini anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lcalza anewknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT cquadalti newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT msannia newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT nehumphreys newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT vabaldassarro newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT agurgone newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT mascolani newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lzanella newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lgiardino newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT ctgross newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT scroci newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT imeloni newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT mgiustetto newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT arenieri newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT llorenzini newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling AT lcalza newknockinmousecarryingthee364xpatientmutationforcdkl5deficiencydisorderneurologicalbehavioralandmolecularprofiling |