Okur-Chung Neurodevelopmental Syndrome-linked CK2α mutations have reduced kinase activity

Abstract The Okur-Chung Neurodevelopmental Syndrome, or OCNDS, is a newly discovered rare neurodevelopmental disorder. It is characterized by developmental delay, intellectual disability, behavioral problems (hyperactivity, repetitive movements and social interaction deficits), hypotonia, epilepsy and language/verbalization deficits. OCNDS is linked to de novo variants in CSNK2A1, that lead to missense or deletion/truncating mutations in the encoded protein, the protein kinase CK2a. Eighteen different missense CK2a mutants have been identified to date, however no biochemical or cell biological studies have yet been performed to clarify the functional impact of such mutations. Here, we show that 15 different missense CK2a mutations lead to varying degrees of loss of kinase activity as recombinant purified proteins and when mutants are ectopically expressed in mammalian cells. We further detect changes in the phosphoproteome of three patient derived fibroblast lines and show that the subcellular localization of CK2a is altered for some of the OCNDS-linked mutants and in patient derived fibroblasts. Our data argue that reduced kinase activity and abnormal localization of CK2a may underlie the OCNDS phenotype.

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A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

Genes ◽

10.3390/genes11030344 ◽

2020 ◽

Vol 11 (3) ◽

pp. 344 ◽

Cited By ~ 2

Author(s):

Emanuela Leonardi ◽

Mariagrazia Bellini ◽

Maria C. Aspromonte ◽

Roberta Polli ◽

Anna Mercante ◽

...

Keyword(s):

Intellectual Disability ◽

Status Epilepticus ◽

Behavioral Problems ◽

Rare Variants ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Somatic Mosaicism ◽

Coiled Coil ◽

Loss Of Function ◽

De Novo Mutations

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

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Missense and truncating variants in CHD5 in a dominant neurodevelopmental disorder with intellectual disability, behavioral disturbances, and epilepsy

Human Genetics ◽

10.1007/s00439-021-02283-2 ◽

2021 ◽

Author(s):

Ilaria Parenti ◽

◽

Daphné Lehalle ◽

Caroline Nava ◽

Erin Torti ◽

...

Keyword(s):

Intellectual Disability ◽

Behavioral Problems ◽

Neuronal Development ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Speech Delay ◽

Nurd Complex ◽

Behavioral Disturbances ◽

Nucleosome Remodeling ◽

Motor Delay

AbstractLocated in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic–clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.

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Optogenetic Control of Protein Kinase Activity in Mammalian Cells

ACS Synthetic Biology ◽

10.1021/sb400090s ◽

2013 ◽

Vol 3 (5) ◽

pp. 280-285 ◽

Cited By ~ 61

Author(s):

Sabrina Wend ◽

Hanna J. Wagner ◽

Konrad Müller ◽

Matias D. Zurbriggen ◽

Wilfried Weber ◽

...

Keyword(s):

Protein Kinase ◽

Mammalian Cells ◽

Kinase Activity ◽

Protein Kinase Activity ◽

Optogenetic Control

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SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

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Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107462 ◽

2021 ◽

pp. jmedgenet-2020-107462

Author(s):

Natalie B Tan ◽

Alistair T Pagnamenta ◽

Matteo P Ferla ◽

Jonathan Gadian ◽

Brian HY Chung ◽

...

Keyword(s):

Intellectual Disability ◽

G Proteins ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Missense Variant ◽

Cellular Functions ◽

Missense Variants ◽

Neurodevelopmental Disease ◽

Genes Encoding ◽

International Data

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

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De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2017.10.003 ◽

2017 ◽

Vol 101 (5) ◽

pp. 768-788 ◽

Cited By ~ 51

Author(s):

Sébastien Küry ◽

Geeske M. van Woerden ◽

Thomas Besnard ◽

Martina Proietti Onori ◽

Xénia Latypova ◽

...

Keyword(s):

Intellectual Disability ◽

Protein Kinase ◽

De Novo ◽

De Novo Mutations

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CBD-enriched cannabis for autism spectrum disorder: an experience of a single center in Turkey and reviews of the literature

Journal of Cannabis Research ◽

10.1186/s42238-021-00108-7 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Serap Bilge ◽

Barış Ekici

Keyword(s):

Autism Spectrum Disorder ◽

Social Interaction ◽

Behavioral Problems ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Average Dose ◽

The Core ◽

Core Symptoms

Abstract Introduction Autism spectrum disorder is a neurodevelopmental disorder characterized by deficits in communication, social interaction, restricted interest, and repetitive behaviors. Although more cases are being diagnosed, no drugs are approved to treat the core symptoms or cognitive and behavioral problems associated with autism. Therefore, there is an urgent need to develop an effective and safe treatment. Objective In this study, we aim to share our 2-year experience with CBD-enriched cannabis treatment in autism and review the latest studies. Materials and methods The study included 33 (27 males, six females) children diagnosed with autism spectrum disorder who were followed up between January 2018 and August 2020. The mean age was 7.7 ± 5.5 years. The average daily dosage of cannabidiol (CBD) was 0.7 mg/kg/day (0.3–2 mg/kg/day). The median duration of treatment was 6.5 months (3–28 months). The preparations used in this study contained full-spectrum CBD and trace elements tetrahydrocannabinol (THC) of less than 3%. Results The outcomes were evaluated before and after treatment based on clinical interviews. At each follow-up visit, parents were asked to evaluate the effectiveness of the CBD-enriched cannabis treatment. According to the parents’ reports, no change in daily life activity was reported in 6 (19.35%) patients. The main improvements of the treatment were as follows: a decrease in behavioral problems was reported in 10 patients (32.2%), an increase in expressive language was reported in 7 patients (22.5%), improved cognition was reported in 4 patients (12,9%), an increase in social interaction was reported in 3 patients (9.6%), and a decrease in stereotypes was reported in 1 patient (3.2%). The parents reported improvement in cognition among patients who adhered to CBD-enriched cannabis treatment for over two years. The antipsychotic drug could be stopped only in one patient who showed mild ASD symptoms. No change could be made in other drug use and doses. Additionally, this study includes an extensive review of the literature regarding CBD treatment in autism spectrum disorder. According to recent studies, the average dose of CBD was 3.8±2.6 mg/kg/day. The ratio of CBD to THC in the used preparations was 20:1. The most significant improvements were seen in the behavioral problems reported in 20–70% of the patients. Conclusion Using lower doses of CBD and trace THC seems to be promising in managing behavioral problems associated with autism. In addition, this treatment could be effective in managing the core symptoms and cognitive functions. No significant side effects were seen at the low doses of CBD-enriched cannabis when compared to other studies.

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Case report : a novel ASXL3 gene variant in a Sudanese boy

BMC Pediatrics ◽

10.1186/s12887-021-03038-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Ke Wu ◽

Yan Cong

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Psychomotor Development ◽

Gene Variant ◽

Feeding Difficulties ◽

Severe Intellectual Disability ◽

Whole Exome

Abstract Background Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. Case presentation The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. Conclusion Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

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Quando il disturbo del neurosviluppo ha un substrato genetico: un caso di sindrome di Kleefstra

Medico e Bambino pagine elettr ◽

10.53126/mebxxiv114 ◽

2021 ◽

Vol 24 (4) ◽

pp. 114-117

Author(s):

Lorena Sorasio ◽

Luisa Franceschi ◽

Lisa Pavinato ◽

Antonella Peduto

Keyword(s):

Intellectual Disability ◽

Exome Sequencing ◽

Point Mutation ◽

Neurodevelopmental Disorders ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Diagnostic Classification ◽

Molecular Cytogenetic ◽

Sequencing Technologies ◽

Molecular Cytogenetic Techniques

Neurodevelopmental disorders (ND) have an important prevalence in children; intellectual disability in particular occurs in a heterogeneous group of genetic conditions. The evolution of molecular cytogenetic techniques and the recent advances in exome sequencing technologies have enormously implemented the possibilities of diagnostic classification in children with cognitive disabilities due to genetics. The paper presents the case of a patient with a neurodevelopmental disorder who was diagnosed with Kleefstra (KS) syndrome, caused by a point mutation de novo of EHMT1 gene.

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