Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 (CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation

Tao, Jiong; Esch, Hilde Van; Hagedorn-Greiwe, M.; Hoffmann, Katharina; Moser, Bettina A.; Raynaud, Martine; Sperner, J.; Fryns, Jean‐Pierre; Schwinger, E.; Gécz, Jozef; Ropers, Hans‐Hilger; Kalscheuer, Vera M.

doi:10.1086/426460

Cited by 277 publications

(244 citation statements)

References 27 publications

(33 reference statements)

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“…67 -70 Moreover, recent data showed that mutations in the cyclin-dependent protein kinase-like 5 (CDKL5/STK9) are responsible for neurodevelopmental disorder with clinical features that are reminiscent of Rett's syndrome. 71,72 Given the clinical overlap resulting from mutation in MECP2 and CDKL5 genes, their involvement in a common genetic and pathogenic pathways has been suspected and further studies showed that spatio-temporal expression of Cdkl5 overlaps with that of Mecp2 and that Mecp2 and Cdkl5 interact in vivo and in vitro. 73 MeCP2 was first identified as a member of the methylCpG-binding domain (MBD) protein family.…”

Section: Genetics and Pathophysiology Of Mr J Chelly Et Almentioning

confidence: 99%

Genetics and pathophysiology of mental retardation

et al. 2006

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Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, associated with functional deficit in adaptive behavior, such as daily-living skills, social skills and communication. Affecting 1-3% of the population and resulting from extraordinary heterogeneous environmental, chromosomal and monogenic causes, MR represents one of the most difficult challenges faced today by clinician and geneticists. Detailed analysis of the Online Mendelian Inheritance in Man database and literature searches revealed more than a thousand entries for MR, and more than 290 genes involved in clinical phenotypes or syndromes, metabolic or neurological disorders characterized by MR. We estimate that many more MR genes remain to be identified. The purpose of this review is to provide an overview on the remarkable progress achieved over the last decade in delineating genetic causes of MR, and to highlight the emerging biological and cellular processes and pathways underlying pathogeneses of human cognitive disorders.

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Section: Genetics and Pathophysiology Of Mr J Chelly Et Almentioning

confidence: 99%

Genetics and pathophysiology of mental retardation

et al. 2006

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“…A small handful of mutations in CDKL5 has been identified recently in patients with an early seizure phenotype of atypical RTT (Archer et al 2006a, b;Evans et al 2005a;Mari et al 2005;Scala et al 2005;Tao et al 2004;Weaving et al 2004). To date, 15 different CDKL5 mutations have been identified in 15 atypical RTT patients with early onset seizure disorder.…”

Section: Cdkl5 Mutation Analysismentioning

confidence: 99%

“…Several reports have identified large gene deletions in RTT patients that escaped detection by PCR-based screening strategies (Laccone et al 2004;Schollen et al 2003). Others have identified mutations in a novel MeCP2 isoform and in CDKL5 (Archer et al 2006a, b;Evans et al 2005a;Kriaucionis et al 2004;Mari et al 2005;Scala et al 2005;Tao et al 2004;Weaving et al 2004). This study reports the results of the mutation analysis of MECP2 and CDKL5 in 121 unrelated Chinese patients with classic or atypical RTT, conducted to obtain a genotypic representation of the mutational spectrum in this population.…”

Section: Introductionmentioning

confidence: 99%

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

Pan

Bao

et al. 2006

J Hum Genet

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Rett syndrome (RTT) is a progressive neurodevelopmental disorder that is caused by mutations in the X-linked methyl-CpG-binding protein2 (MECP2) gene. In this study, the MECP2 sequences in 121 unrelated Chinese patients with classical or atypical RTT were screened for deletions and mutations. In all, we identified 45 different MECP2 mutations in 102 of these RTT patients. The p. T158M mutation (15.7%) was the most common, followed in order of frequency by p. R168X (11.8%), p. R133C (6.9%), p. R270X (6.9%), p. G269fs (6.9%), p. R255X (4.9%), and p. R306C (3.9%). In addition, we identified five novel MECP2 mutations: three missense (p. K305E, p. V122M, p. A358T), one insertion (c.45-46ins-GGAGGA), and one 22 bp deletion (c.881-902del22). Large deletions represented 10.5% of all identified MECP2 mutations. Conversely, mutations in exon 1 appeared to be rare (0.9%). The remaining cases without MECP2 mutations were screened for the cyclin-dependent kinase-like 5 (CDKL5) gene using denaturing high-performance liquid chromatography (DHPLC). One synonymous mutation (p. I72I) was found in exon 5, suggesting that CDKL5 is a rare cause of RTT. The overall MECP2 mutation detection rate for this patient series was 84.3:87.9% in 107 classical RTT cases and 57.1% in 14 atypical RTT cases. Moreover, there were two patients with homozygous mutations and normal female karyotypes. However, we did not pinpoint a significant relationship between genotype and phenotype in these cases.

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“…Point mutations or genomic deletions in MECP2 have been identified in greater than 90% of patients with typical Rett syndrome. 1,2 In 30-50% of patients with atypical Rett syndrome, 3 negative for alterations in MECP2, intragenic changes in CDKL5 [4][5][6][7][8] or in FOXG1 [9][10][11] have been reported.…”

Section: Introductionmentioning

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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Mutations in the X-Linked Cyclin-Dependent Kinase–Like 5 (CDKL5/STK9) Gene Are Associated with Severe Neurodevelopmental Retardation

Cited by 277 publications

References 27 publications

Genetics and pathophysiology of mental retardation

Genetics and pathophysiology of mental retardation

MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

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