The CCR4-NOT complex, crucial in gene expression regulation, includes CNOT3, a subunit linked to neurodevelopmental disorders when mutated. This study investigates 51 patients from 42 families with heterozygous CNOT3 variants, aiming to expand the understanding of CNOT3-related neurodevelopmental disorders and explore genotype-phenotype correlations. Patients originated from various countries, reflecting the disorder's global significance. All patients exhibited developmental delays, particularly in the language area. Intellectual disability was found in 87% of patients and was typically mild to moderate. Behavioral issues, including autism spectrum disorders and attention deficits, were common, affecting over half of the patients. Dysmorphic features were highlighted and may help establishing the diagnosis. Epilepsy was uncommon (10%). Twenty-eight novel variants were identified, including missense, nonsense, frameshift, intronic variations and a deletion of 12 exons. Missense variants clustered at the N- and C-terminal regions of the protein, indicating critical functional roles. No clear genotype-phenotype correlation was observed, suggesting that all identified variants resulted in a loss-of-function effect. Finally, this work delineates the clinical and molecular spectrum of CNOT3-related disorders thanks to an in-depth characterization of a large cohort. Further research will be necessary to understand the functional consequences of the variants and enhance patient long-term outcomes.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• missense mutace MeSH
• mladiství MeSH
• neurovývojové poruchy * genetika   patologie   MeSH
• předškolní dítě MeSH
• represorové proteiny * genetika   MeSH
• transkripční faktory * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CNOT3 protein, human MeSH Prohlížeč
• represorové proteiny * MeSH
• transkripční faktory * MeSH

In a recent Cell article, Baluapuri et al.1 show that loss of the Integrator (INT) complex activates the integrated stress response via double-stranded RNA from incomplete pre-mRNAs, revealing a link to INT-related neurodevelopmental diseases and potential therapeutic targets.

• MeSH
• dvouvláknová RNA metabolismus   genetika   MeSH
• fyziologický stres * MeSH
• lidé MeSH
• neurovývojové poruchy * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dvouvláknová RNA MeSH

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

• Klíčová slova
• ACTL6B, Autism, BAFopathies, Epileptic-dyskinetic encephalopathy, Ribosomopathies,
• MeSH
• dítě MeSH
• dominantní geny MeSH
• fenotyp MeSH
• geny recesivní MeSH
• jaderné proteiny * genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mladiství MeSH
• mozek patologie   MeSH
• mutace MeSH
• nemoci mozku * genetika   patologie   MeSH
• neurovývojové poruchy * genetika   MeSH
• předškolní dítě MeSH
• vývojové poruchy u dětí * genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• jaderné proteiny * MeSH

Mutations in CACNA1C, the gene encoding Cav1.2 voltage-gated calcium channels, are associated with a spectrum of disorders, including Timothy syndrome and other neurodevelopmental and cardiac conditions. In this study, we report a child with a de novo heterozygous missense variant (c.1973T > C; L658P) in CACNA1C, presenting with refractory epilepsy, global developmental delay, hypotonia, and multiple systemic abnormalities, but without overt cardiac dysfunction. Electrophysiological analysis of the recombinant Cav1.2 L658P variant revealed profound gating alterations, most notably a significant hyperpolarizing shift in the voltage dependence of activation and inactivation. Additionally, molecular modeling suggested that the L658P mutation disrupts interactions within the IIS5 transmembrane segment, reducing the energy barrier for state transitions and facilitating channel opening at more negative voltages. These findings establish L658P as a pathogenic CACNA1C variant primarily associated with severe neurological dysfunction and expands the phenotypic spectrum of CACNA1C-related disorders.

• Klíčová slova
• CACNA1C, Calcium channel, Cav1.2, Channelopathies, Electrophysiology, L658P,
• MeSH
• dítě MeSH
• gating iontového kanálu MeSH
• HEK293 buňky MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• molekulární modely MeSH
• mutace * genetika   MeSH
• neurovývojové poruchy * genetika   patofyziologie   MeSH
• sekvence aminokyselin MeSH
• vápníkové kanály - typ L * genetika   chemie   metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CACNA1C protein, human MeSH Prohlížeč
• vápníkové kanály - typ L * MeSH

PURPOSE: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.

• Klíčová slova
• CACNA1G gene, Cerebellum, Neurodevelopment, Spinocerebellar ataxia, T-type voltage-gated calcium channel,
• MeSH
• dítě MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mladiství MeSH
• neurovývojové poruchy * genetika   MeSH
• předškolní dítě MeSH
• spinocerebelární ataxie * genetika   MeSH
• vápníkové kanály - typ T * genetika   metabolismus   chemie   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CACNA1G protein, human MeSH Prohlížeč
• vápníkové kanály - typ T * MeSH

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

• Klíčová slova
• autophagy, intracellular trafficking, neurodevelopmental disorders, viral immunity,
• MeSH
• cytoplazmatické dyneiny * genetika   MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace MeSH
• neurovývojové poruchy genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytoplazmatické dyneiny * MeSH
• DYNC1H1 protein, human MeSH Prohlížeč

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp * MeSH
• histony * genetika   MeSH
• lidé MeSH
• mentální retardace genetika   patologie   MeSH
• mladiství MeSH
• neurodegenerativní nemoci genetika   patologie   MeSH
• neurovývojové poruchy genetika   patologie   MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• histony * MeSH

N-Methyl-d-aspartate receptors (NMDARs), encoded by GRIN genes, are ionotropic glutamate receptors playing a critical role in synaptic transmission, plasticity, and synapse development. Genome sequence analyses have identified variants in GRIN genes in patients with neurodevelopmental disorders, but the underlying disease mechanisms are not well understood. Here, we have created and evaluated a transgenic mouse line carrying a missense variant Grin2bL825V , corresponding to a de novo GRIN2B variant encoding GluN2B(L825V) found in a patient with intellectual disability (ID) and autism spectrum disorder (ASD). We used HEK293T cells expressing recombinant receptors and primary hippocampal neurons prepared from heterozygous Grin2bL825V/+ (L825V/+) and wild-type (WT) Grin2b+/+ (+/+) male and female mice to assess the functional impact of the variant. Whole-cell NMDAR currents were reduced in neurons from L825V/+ compared with +/+ mice. The peak amplitude of NMDAR-mediated evoked excitatory postsynaptic currents (NMDAR-eEPSCs) was unchanged, but NMDAR-eEPSCs in L825V/+ neurons had faster deactivation compared with +/+ neurons and were less sensitive to a GluN2B-selective antagonist ifenprodil. Together, these results suggest a decreased functional contribution of GluN2B subunits to synaptic NMDAR currents in hippocampal neurons from L825V/+ mice. The analysis of the GluN2B(L825V) subunit surface expression and synaptic localization revealed no differences compared with WT GluN2B. Behavioral testing of mice of both sexes demonstrated hypoactivity, anxiety, and impaired sensorimotor gating in the L825V/+ strain, particularly affecting males, as well as cognitive symptoms. The heterozygous L825V/+ mouse offers a clinically relevant model of GRIN2B-related ID/ASD, and our results suggest synaptic-level functional changes that may contribute to neurodevelopmental pathology.

• Klíčová slova
• GluN2B, NMDA receptors, autism spectrum disorder, mouse model, synaptic transmission,
• MeSH
• excitační postsynaptické potenciály fyziologie   MeSH
• HEK293 buňky MeSH
• hipokampus metabolismus   MeSH
• lidé MeSH
• missense mutace MeSH
• myši inbrední C57BL MeSH
• myši transgenní * MeSH
• myši MeSH
• neurony metabolismus   MeSH
• neurovývojové poruchy * genetika   patofyziologie   metabolismus   MeSH
• receptory N-methyl-D-aspartátu * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• NR2B NMDA receptor MeSH Prohlížeč
• receptory N-methyl-D-aspartátu * MeSH

N-methyl-D-aspartate receptors (NMDARs) are a subtype of ionotropic glutamate receptors critical for synaptic transmission and plasticity, and for the development of neural circuits. Rare or de-novo variants in GRIN genes encoding NMDAR subunits have been associated with neurodevelopmental disorders characterized by intellectual disability, developmental delay, autism, schizophrenia, or epilepsy. In recent years, some disease-associated variants in GRIN genes have been characterized using recombinant receptors expressed in non-neuronal cells, and a few variants have also been studied in neuronal preparations or animal models. Here we review the current literature on the functional evaluation of human disease-associated variants in GRIN1, GRIN2A and GRIN2B genes at all levels of analysis. Focusing on the impact of different patient variants at the level of receptor function, we discuss effects on receptor agonist and co-agonist affinity, channel open probability, and receptor cell surface expression. We consider how such receptor-level functional information may be used to classify variants as gain-of-function or loss-of-function, and discuss the limitations of this classification at the synaptic, cellular, or system level. Together this work by many laboratories worldwide yields valuable insights into NMDAR structure and function, and represents significant progress in the effort to understand and treat GRIN disorders. Keywords: NMDA receptor , GRIN genes, Genetic variants, Electrophysiology, Synapse, Animal models.

• MeSH
• genetická predispozice k nemoci MeSH
• genetická variace MeSH
• lidé MeSH
• neurovývojové poruchy genetika   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• receptory N-methyl-D-aspartátu * genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• GRIN1 protein, human MeSH Prohlížeč
• N-methyl D-aspartate receptor subtype 2A MeSH Prohlížeč
• NR2B NMDA receptor MeSH Prohlížeč
• proteiny nervové tkáně MeSH
• receptory N-methyl-D-aspartátu * MeSH

BACKGROUND: Heterozygous loss-of-function variants in CHD8 have been associated with a syndromic neurodevelopmental-disease spectrum, collectively referred to as CHD8-related neurodevelopmental disorders. Several different clinical manifestations, affecting neurodevelopmental and systemic domains, have been described, presenting with highly variable expressivity. Some expressions are well established and comprise autism spectrum disorders, psychomotor delay with cognitive impairment, postnatal overgrowth with macrocephaly, structural brain abnormalities, gastrointestinal disturbances, and behavioral and sleep-pattern problems. However, the complete phenotypic spectrum of CHD8-related disorders is still undefined. In 2021, our group described two singular female patients with CHD8-related neurodevelopmental disorder and striking dystonic manifestations, prompting the suggestion that dystonia should be considered a possible component of this condition. CASE SERIES PRESENTATION: We describe three additional unrelated female individuals, each carrying a different CHD8 frameshift variant and whose clinical presentations were primarily characterized by young-onset dystonia. Their dystonic manifestations were remarkably heterogeneous and ranged from focal, exercise-dependent, apparently isolated forms to generalized permanent phenotypes accompanied by spasticity and tremor. Neurocognitive impairment and autistic behaviors, typical of CHD8-related disorders, were virtually absent or at the mild end of the spectrum. CONCLUSIONS: This work validates our previous observation that dystonia is part of the phenotypic spectrum of CHD8-related neurodevelopmental disorders with potential female preponderance, raising new challenges and opportunities in the diagnosis and management of this condition. It also highlights the importance of in-depth neurologic phenotyping of patients carrying variants associated with neurodevelopmental disorders, as the connection between neurodevelopmental and movement disorders is proving closer than previously appreciated.

• Klíčová slova
• CHD8, CHD8-NDD, Autism, Dystonia, Exome sequencing, Movement disorders,
• MeSH
• dítě MeSH
• DNA vazebné proteiny * genetika   MeSH
• dospělí MeSH
• dystonické poruchy genetika   diagnóza   patofyziologie   komplikace   MeSH
• dystonie genetika   etiologie   patofyziologie   diagnóza   MeSH
• fenotyp * MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• neurovývojové poruchy genetika   diagnóza   MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• CHD8 protein, human MeSH Prohlížeč
• DNA vazebné proteiny * MeSH
• transkripční faktory MeSH