A novel mutation in the X‐linked cyclin‐dependent kinase‐like 5 (<i>CDKL5</i>) gene associated with a severe Rett phenotype

Sprovieri, T.; Conforti, Francesca Luisa; Fiumara, Agata; Mazzei, R.; Ungaro, C; Citrigno, Luigi; Muglia, M.; Arena, Alessia; Quattrone, Aldo

doi:10.1002/ajmg.a.32711

Cited by 21 publications

(15 citation statements)

References 20 publications

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“…Mutations of CDKL5 have been associated with several X-linked neurodevelopmental disorders, as well as ASD (Weaving et al, 2004; Scala et al, 2005; Archer et al, 2006; Russo et al, 2009; Sprovieri et al, 2009; Schaaf et al, 2011; Bahi-Buisson and Bienvenu, 2012; Bartnik et al, 2012; Maortua et al, 2012; Carvill et al, 2013; Epi et al, 2013; Piton et al, 2013; Zhao et al, 2014; Codina-Sola et al, 2015; Szafranski et al, 2015). Expression of CDKL5 is enriched in the brain and increases gradually following development (Lin et al, 2005; Rusconi et al, 2008).…”

Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) comprises a range of neurological conditions that affect individuals’ ability to communicate and interact with others. People with ASD often exhibit marked qualitative difficulties in social interaction, communication, and behavior. Alterations in neurite arborization and dendritic spine morphology, including size, shape, and number, are hallmarks of almost all neurological conditions, including ASD. As experimental evidence emerges in recent years, it becomes clear that although there is broad heterogeneity of identified autism risk genes, many of them converge into similar cellular pathways, including those regulating neurite outgrowth, synapse formation and spine stability, and synaptic plasticity. These mechanisms together regulate the structural stability of neurons and are vulnerable targets in ASD. In this review, we discuss the current understanding of those autism risk genes that affect the structural connectivity of neurons. We sub-categorize them into (1) cytoskeletal regulators, e.g., motors and small RhoGTPase regulators; (2) adhesion molecules, e.g., cadherins, NCAM, and neurexin superfamily; (3) cell surface receptors, e.g., glutamatergic receptors and receptor tyrosine kinases; (4) signaling molecules, e.g., protein kinases and phosphatases; and (5) synaptic proteins, e.g., vesicle and scaffolding proteins. Although the roles of some of these genes in maintaining neuronal structural stability are well studied, how mutations contribute to the autism phenotype is still largely unknown. Investigating whether and how the neuronal structure and function are affected when these genes are mutated will provide insights toward developing effective interventions aimed at improving the lives of people with autism and their families.

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Section: Signaling Molecules Actively Regulate Dendritic Spine and Dementioning

confidence: 99%

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

Lin

Frei

Kilander

et al. 2016

Front. Cell. Neurosci.

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“…Infantile spasms and refractory myoclonic epilepsy are frequent during the course of epilepsy but not always present in CDKL5 mutation patients ( tables 1 and 2 ) [Tao et al, 2004;Weaving et al, 2004;Evans et al, 2005;Mari et al, 2005;Scala et al, 2005;Archer et al, 2006;Buoni et al, 2006;Nectoux et al, 2006;Grosso et al, 2007;Bahi-Buisson et al, 2008b;Pintaudi et al, 2008;Nemos et al, 2009;Russo et al, 2009;Sprovieri et al, 2009;Bahi-Buisson et al, 2010;Mei et al, 2010;Psoni et al, 2010;Arts, 2011;Castren et al, 2011;Melani et al, 2011;Rademacher et al, 2011]. Patients who presented with a disrupted CDKL5 gene due to unbalanced translocations were excluded.…”

Section: Common and Rare Featuresmentioning

confidence: 99%

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

Bahi-Buisson¹,

Bienvenu

2011

Mol Syndromol

101

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Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 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. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.

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“…2 Mutations in CDKL5 (OMIM# 300203) are X-linked dominant and have been described in females with severe neurodevelopmental disorders characterized by early-onset seizures, infantile spasms and severe psychomotor impairments, and Rett Syndrome (RTT)-like phenotypes. 3 The phenotypic resemblance to Rett syndrome is likely related to similar function of the CDKL5 and MeCP2 proteins in the molecular pathways and regional pattern of expression during neurodevelopment. 4,5 Recently, copy number variations (CNVs) involving the CDKL5 gene have been reported in girls with severe epilepsy and a RTT-like phenotype.…”

mentioning

confidence: 99%

Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females

Bartnik¹,

Derwińska²,

Gos³

et al. 2011

Genetics in Medicine

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Purpose: Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT)-like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5. Methods: We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5. Results: We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5. Conclusion: We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders. Genet T he cyclin-dependent kinase-like 5 (CDKL5) gene (also known as seronine-threonine kinase 9) encodes a protein of 1030 amino acids with highly conserved serine-threonine kinase domain in the N-terminal region and a large C-terminal region involved in either the catalytic activity or the subcellular localization. 1 CDKL5 is particularly expressed in the brain and has homology to the mitogen-activated protein kinase and CDK families. 2 Mutations in CDKL5 (OMIM# 300203) are X-linked dominant and have been described in females with severe neurodevelopmental disorders characterized by early-onset seizures, infantile spasms and severe psychomotor impairments, and Rett Syndrome (RTT)-like phenotypes. 3 The phenotypic resemblance to Rett syndrome is likely related to similar function of the CDKL5 and MeCP2 proteins in the molecular pathways and regional pattern of expression during neurodevelopment. 4,5 Recently, copy number variations (CNVs) involving the CDKL5 gene have been reported in girls with severe epilepsy and a RTT-like phenotype. The increasing availability of array comparative genomic hybridization (CGH) has led to several publications describing different deletions in CDKL5 in females. 6 -9 These data emphasize that deletion CNVs involving CDKL5 are more common than first appreciated, especially in females.CDKL5 mutations have been found very rarely in males, suggesting that nullisomy might be incompatible with life. To date, only two frameshifts and four missense mutations have been reported in males with severe encephalopathy and early-onset intractable epilepsy. 10 -13 In addition, an approximately 2.8-Mb deletion involving CDKL5 and 15 other genes has been reported in a boy with severe encephalopathy, tetralogy of Fallot, and bilateral cataracts. 14 Also, an approximately 136-kb deletion disrupting exons 17-20 of CDKL5 and the RS1 and PPEF1 genes has been described in a male with retinoschisis and epilepsy. 15 We report ...

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A novel mutation in the X‐linked cyclin‐dependent kinase‐like 5 (CDKL5) gene associated with a severe Rett phenotype

Cited by 21 publications

References 20 publications

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

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

Early-onset seizures due to mosaic exonic deletions of CDKL5 in a male and two females

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