Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder
CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2023.1231493/full |
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| author | Valeria Ruggiero Valeria Ruggiero Claudio Fagioli Claudio Fagioli Stefano de Pretis Stefano de Pretis Valerio Di Carlo Nicoletta Landsberger Nicoletta Landsberger Daniele Zacchetti Daniele Zacchetti |
| author_facet | Valeria Ruggiero Valeria Ruggiero Claudio Fagioli Claudio Fagioli Stefano de Pretis Stefano de Pretis Valerio Di Carlo Nicoletta Landsberger Nicoletta Landsberger Daniele Zacchetti Daniele Zacchetti |
| author_sort | Valeria Ruggiero |
| collection | DOAJ |
| description | CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5′UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein. |
| first_indexed | 2024-03-11T15:06:39Z |
| format | Article |
| id | doaj.art-3561e301f749442799dc30d47326ef82 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-03-11T15:06:39Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-3561e301f749442799dc30d47326ef822023-10-30T04:55:26ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022023-10-011710.3389/fncel.2023.12314931231493Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorderValeria Ruggiero0Valeria Ruggiero1Claudio Fagioli2Claudio Fagioli3Stefano de Pretis4Stefano de Pretis5Valerio Di Carlo6Nicoletta Landsberger7Nicoletta Landsberger8Daniele Zacchetti9Daniele Zacchetti10Vita-Salute San Raffaele University, Milan, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyDepartment of Medical Biotechnology and Translational Medicine, University of Milan, Segrate, ItalyVita-Salute San Raffaele University, Milan, ItalyDivision of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, ItalyCDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5′UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein.https://www.frontiersin.org/articles/10.3389/fncel.2023.1231493/fullCDKL5translation initiation5′UTRCDKL5 deficiency disorderIRES |
| spellingShingle | Valeria Ruggiero Valeria Ruggiero Claudio Fagioli Claudio Fagioli Stefano de Pretis Stefano de Pretis Valerio Di Carlo Nicoletta Landsberger Nicoletta Landsberger Daniele Zacchetti Daniele Zacchetti Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder Frontiers in Cellular Neuroscience CDKL5 translation initiation 5′UTR CDKL5 deficiency disorder IRES |
| title | Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder |
| title_full | Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder |
| title_fullStr | Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder |
| title_full_unstemmed | Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder |
| title_short | Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder |
| title_sort | complex cdkl5 translational regulation and its potential role in cdkl5 deficiency disorder |
| topic | CDKL5 translation initiation 5′UTR CDKL5 deficiency disorder IRES |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2023.1231493/full |
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