&lt;i&gt;CDKL5&lt;/i&gt;-Related Disorders: From Clinical Description to Molecular Genetics

Bahi-Buisson, N.; Bienvenu, Thierry

doi:10.1159/000331333

Cited by 90 publications

(118 citation statements)

References 98 publications

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“…Cdkl5 -/y mice display hyperactivity, motor defects, reduced anxiety, decreased sociability, and impaired learning and memory. These phenotypes have been described in other ASD and RTT mouse models (2, 16, 17, 19, 26) and may mimic the absence of hand skills, intellectual disability, hyperactivity, and poor response to social interactions that have been described in CDKL5 patients (12,41). While video-EEG monitoring revealed an absence of spontaneous seizures in Cdkl5 -/y mice, ERP analysis showed attenuated and delayed ERP polarity peaks suggestive of impaired neuronal connectivity, which is consistent with findings in ASD and RTT patients (30,31) and animal models (19,28,29).…”

Section: Discussionmentioning

confidence: 70%

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Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang

Allen²,

Goffin³

et al. 2012

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

182

247

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in neurodevelopmental disorders including atypical Rett syndrome (RTT), autism spectrum disorders (ASDs), and early infantile epileptic encephalopathy. The biological function of CDKL5 and its role in the etiology of these disorders, however, remain unclear. Here we report the development of a unique knockout mouse model of CDKL5-related disorders and demonstrate that mice lacking CDKL5 show autistic-like deficits in social interaction, as well as impairments in motor control and fear memory. Neurophysiological recordings reveal alterations in event-related potentials (ERPs) similar to those observed in RTT and ASDs. Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKTmammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function. These data demonstrate that CDKL5 regulates signal transduction pathways and mediates autistic-like phenotypes and together establish a causal role for Cdkl5 loss-of-function in neurodevelopmental disorders.C yclin-dependent kinase-like 5 (CDKL5) is an X-linked gene associated with early infantile epileptic encephalopathy 2 (EIEE2) (1), atypical Rett syndrome (RTT) (2), and autism spectrum disorders (ASDs) (3, 4). Patients with CDKL5 mutations display a heterogenous array of clinical phenotypes, the most prominent of which include early-onset seizures, intellectual disability, and autistic features (5).CDKL5 is a serine/threonine (S/T) kinase that is highly expressed in the brain (6). In vitro studies have demonstrated that CDKL5 may mediate the phosphorylation of methyl-CpG binding protein 2 (MeCP2) (7), DNA methyltransferase 1 (DNMT1) (8), and netrin-G1 ligand (NGL-1) (9). RNAi-mediated knockdown studies show that CDKL5 can regulate neuronal outgrowth and synapse stability (9, 10). Despite these proposed functions, the exact role of CDKL5 in the phosphorylation of MeCP2 (7, 11) and in dendritic outgrowth (9, 10) remains unclear, and thus requires further investigation. The limited understanding of CDKL5 function and its associated signal transduction pathways has hindered the development of therapeutics for CDKL5-related disorders. Current treatments focus on managing symptoms and reducing seizure frequency, but have limited effectiveness (12).To investigate the function of CDKL5 in a disease model and identify potential avenues of therapeutic intervention, we developed a Cdkl5 knockout mouse. We found that mice lacking CDKL5 show autistic-like behavioral abnormalities, deficits in neural circuit communication, and alterations in multiple signal transduction pathways. We establish a causal link between Cdkl5 loss-of-function and disease-related phenotypes and identify the AKT-mammalian target of rapamycin (mTOR) pathway as a unique candidate for targeted therapeutic intervention of CDKL5-related disorders. ResultsGeneration of Cdkl5 Knockout Mice. To investigate the pathophysiology underlying CDKL5-related disorders, we generated ...

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Section: Discussionmentioning

confidence: 70%

“…The limited understanding of CDKL5 function and its associated signal transduction pathways has hindered the development of therapeutics for CDKL5-related disorders. Current treatments focus on managing symptoms and reducing seizure frequency, but have limited effectiveness (12).…”

mentioning

confidence: 99%

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Wang

Allen²,

Goffin³

et al. 2012

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

182

247

View full text Add to dashboard Cite

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“…18,[39][40][41] The vast majority of genetic alterations in CDKL5 45 reported a CDKL5 alteration in a 47,XXY boy with the early-onset seizure variant of Rett syndrome and concluded that a random pattern of XCI did not influence the severity of the disease. Skewed XCI has been proposed to explain the observed phenotypic variability in some females heterozygous for a mutated or deleted CDKL5 allele.…”

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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“…1 To date, with 480 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech, and Rett-like features such as hand stereotypies and deceleration of head growth.…”

Section: Introductionmentioning

confidence: 99%

Mutations in the C-terminus of CDKL5: proceed with caution

et al. 2013

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Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and earlyonset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3 0 -end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3 0 -end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5 115 protein may have minor or no significance. It is probable that screening of exons 19-21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome.

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<i>CDKL5</i>-Related Disorders: From Clinical Description to Molecular Genetics

Cited by 90 publications

References 98 publications

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

Mutations in the C-terminus of CDKL5: proceed with caution

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