Identification and Characterization of a Novel Serine– Threonine Kinase Gene from the Xp22 Region

Montini, Eugenio; Andolfi, Grazia; Caruso, Antonio; Buchner, Georg; Walpole, Susannah M.; Mariani, Margherita; Consalez, G. Giacomo; Trump, Dorothy; Ballabio, Andrea; Franco, Brunella

doi:10.1006/geno.1998.5391

Cited by 127 publications

(124 citation statements)

References 22 publications

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“…To identify the minimal binding motif, we generated a series of N-terminal deletion mutants of PSD-95 with GFP fused to their C termini and tested their interaction with CDKL5. We observed that PSD-95 (amino acids 1-21), PSD-95 (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], and PSD-95 (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] bound to CDKL5 at comparable levels (Fig. 2B).…”

Section: Psd-95mentioning

confidence: 79%

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Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Yingguo¹,

Li²,

Wang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, downregulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation-dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders.M utations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been identified in patients with severe neurodevelopmental disorders, including an early-onset variant of Rett syndrome (1, 2). The predicted protein encoded by CDKL5 gene belongs to the CDKL family that comprises five members, CDKL1 to CDKL5 (3). The expression of CDKL5 is enriched in human and rat brain (4, 5). In murine, CDKL5 is expressed at low levels in embryonic stages and its expression is markedly upregulated during postnatal development (5, 6). Loss-of-function studies using RNA interference (RNAi) revealed that CDKL5 is required for neurite growth and excitatory synapse stability (5, 7). Deficiency of CDKL5 in mice leads to autistic-like phenotypes, indicating a causal role for CDKL5 loss of function in disease (8).Several interacting partners of CDKL5 have been reported, including the Rett syndrome-related protein methyl-CpG binding protein 2 (MeCP2) (9), the DNA methyltransferase Dnmt1 (10), and netrin-G1 ligand (NGL-1) (7). All of the three proteins are potential substrates for CDKL5, at least as demonstrated in vitro, suggesting that CDKL5 elicits its function by phosphorylating target proteins. Although the kinase activity of CDKL5 is required for its function and is impaired by some mutations identified in patients (7, 11), the regulation of CDKL5 seems to be equally important in the pathogenesis of disease, which is suggested by a number of pathogenic mutations identified within its C-terminal region (12). Therefore, further identification of CDKL5-interacting proteins may uncover the regulatory mechanisms for CDKL5, which is an important step toward the understanding of the causes of CDKL5-related disorders.The multidomain protein postsynaptic density (PSD)-95 is a major scaffold in the postsynaptic density (PSD) (13), and has been extensively investigated during the past decade. These studies have established the essential role of PSD-95 in syn...

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Section: Psd-95mentioning

confidence: 79%

“…The predicted protein encoded by CDKL5 gene belongs to the CDKL family that comprises five members, CDKL1 to CDKL5 (3). The expression of CDKL5 is enriched in human and rat brain (4,5). In murine, CDKL5 is expressed at low levels in embryonic stages and its expression is markedly upregulated during postnatal development (5,6).…”

mentioning

confidence: 99%

Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Yingguo¹,

Li²,

Wang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…12 Conversely, isoform II, transcribed from exons 1a and 1b (but not exon 1), is only expressed at very low levels in human fetal brain and testes. 46,47 It remains to be determined in what brain compartment(s) and in which cells this isoform is predominantly expressed. The phenotypic similarities observed in male patient 5 and female patients 6 and 7 with the duplication of CDKL5 isoform II may result from abnormalities in spatiotemporal functions or interactions of CDKL5 during fetal brain development.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Szafrański

Golla²,

Jin

et al. 2014

Eur J Hum Genet

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Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667 kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.

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“…Expression studies demonstrated that CDKL5 was transcribed in several tissues, including brain (1). However, the possible link between CDKL5 and human diseases was drawn only few years later when balanced translocating events disrupting the gene were identified in two female patients affected by severe infantile spasms and mental retardation (2).…”

mentioning

confidence: 99%

Functional Consequences of Mutations inCDKL5, an X-linked Gene Involved in Infantile Spasms and Mental Retardation

et al. 2006

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.X-linked cyclin-dependent kinase-like 5 (CDKL5, 3 previously named STK9) was originally identified in a transcriptional mapping project focused on the human chromosome Xp22.3-p21.3, spanning a region critical for several diseases. Expression studies demonstrated that CDKL5 was transcribed in several tissues, including brain (1). However, the possible link between CDKL5 and human diseases was drawn only few years later when balanced translocating events disrupting the gene were identified in two female patients affected by severe infantile spasms and mental retardation (2). Retrospectively, a previous publication had identified a large deletion involving CDKL5 in a male patient with X-linked retinoschisis and seizure (3); it has recently been hypothesized that retinoschisis is due to deletion of the XLRS1 gene, whereas epilepsy is caused by truncation of at least the last exon of CDKL5 (2). The importance of CDKL5 in early onset seizures and severe mental retardation in females has been further reinforced by five recent reports linking mutations in CDKL5 to patients with Rett syndrome but only in those affected by a variant form characterized by seizure onset before 6 months of age (4 -8). Very recently the frequency of CDKL5 mutations in patients affected by infantile spasms or early onset epilepsy of unknown cause has been investigated. The identification of several novel lik...

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Identification and Characterization of a Novel Serine– Threonine Kinase Gene from the Xp22 Region

Cited by 127 publications

References 22 publications

Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Palmitoylation-dependent CDKL5–PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Functional Consequences of Mutations inCDKL5, an X-linked Gene Involved in Infantile Spasms and Mental Retardation

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