The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

Fehr, Stephanie; Wilson, Meredith; Downs, Jenny; Williams, Simon; Murgia, Alessandra; Sartori, Stefano; Vecchi, Marilena; Ho, Gladys; Polli, Roberta; Psoni, Stavroula; Bao, Xinhua; Klerk, Nicholas de; Leonard, Helen; Christodoulou, John

doi:10.1038/ejhg.2012.156

Cited by 246 publications

(319 citation statements)

References 49 publications

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“…Our data support an increasing awareness that CDKL5-related disorders are an independent clinical entity with an independent pathogenic mechanism, rather than a subclass of RTT. Strikingly, only less than one-quarter of individuals with CDKL5 mutations meet the criteria for the early-onset seizure variant of RTT (53,54). Its genetic link to neurodevelopmental disorders and recent identification as an ASD hotspot for balanced chromosomal rearrangements (4) highlight the need to characterize CDKL5 biological function, understand the mechanisms underlying CDKL5-related disorders, and identify effective therapies targeted toward slowing or reversing disease progression.…”

Section: Discussionmentioning

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.

186

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: 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.

186

247

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“…CDKL5 has been shown to promote neuronal survival (66), neurite outgrowth (49), dendritic spine formation (50,51), and is an excellent example of a Mib1 interaction partner that regulates both cytoskeleton morphology and synaptic activity-bridging these two interrelated processes. Mutations in CDKL5 cause extreme variants of Rett Syndrome (67), and EIEE2 (68) which are severe and progressive forms of mental retardation. Our experiments show that when Mib1 is in abundance relative to CDKL5, dendritic spine outgrowth is impaired.…”

Section: Discussionmentioning

confidence: 99%

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Mertz¹,

Tan

Pagala

et al. 2015

Molecular & Cellular Proteomics

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The mind bomb 1 (Mib1) ubiquitin ligase is essential for controlling metazoan development by Notch signaling and possibly the Wnt pathway. It is also expressed in postmitotic neurons and regulates neuronal morphogenesis and synaptic activity by mechanisms that are largely unknown. We sought to comprehensively characterize the Mib1 interactome and study its potential function in neuron development utilizing a novel sequential elution strategy for affinity purification, in which Mib1 binding proteins were eluted under different stringency and then quantified by the isobaric labeling method. The strategy identified the Mib1 interactome with both deep coverage and the ability to distinguish high-affinity partners from low-affinity partners. A total of 817 proteins were identified during the Mib1 affinity purification, including 56 high-affinity partners and 335 low-affinity partners, whereas the remaining 426 proteins are likely copurified contaminants or extremely weak binding proteins. The analysis detected all previously known Mib1-interacting proteins and revealed a large number of novel components involved in Notch and Wnt pathways, endocytosis and vesicle transport, the ubiquitin-proteasome system, cellular morphogenesis, and synaptic activities. Immunofluorescence studies further showed colocalization of Mib1 with five selected proteins: the Usp9x (FAM) deubiquitinating enzyme, alpha-, beta-, and delta-catenins, and CDKL5. Mutations of CDKL5 are associated with early infantile epileptic encephalopathy-2 (EIEE2), a severe form of mental retardation. We found that the expression of Mib1 downregulated the protein level of CDKL5 by ubiquitination, and antagonized CDKL5 function during the formation of dendritic spines. Thus, the sequential elution strategy enables biochemical characterization of protein interac-

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“…The final component of these most recent criteria 6 provides further clinical description of some of the original "variant" forms, two of which, the early seizure onset variant now recognised as the CDKL5 disorder 113 and the congenital variant, mostly caused by mutations in FOXG1, 114 must now be considered only as Rett-related disorders. 111 The third atypical form, the Zappella or preserved speech variant, 107 is most often associated with a p.Arg133Cys mutation 115 or a C terminal deletion (see Fig.…”

Section: Clinical Features and Diagnosismentioning

confidence: 99%

Clinical and biological progress over 50 years in Rett syndrome

2016

Self Cite

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It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

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The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy

Cited by 246 publications

References 49 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

Sequential Elution Interactome Analysis of the Mind Bomb 1 Ubiquitin Ligase Reveals a Novel Role in Dendritic Spine Outgrowth

Clinical and biological progress over 50 years in Rett syndrome

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