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.

• 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

The chicken Tva cell surface protein, a member of the low-density lipoprotein receptor family, has been identified as an entry receptor for avian leukosis virus of classic subgroup A and newly emerging subgroup K. Because both viruses represent an important concern for the poultry industry, we introduced a frame-shifting deletion into the chicken tva locus with the aim of knocking-out Tva expression and creating a virus-resistant chicken line. The tva knock-out was prepared by CRISPR/Cas9 gene editing in chicken primordial germ cells and orthotopic transplantation of edited cells into the testes of sterilized recipient roosters. The resulting tva -/- chickens tested fully resistant to avian leukosis virus subgroups A and K, both in in vitro and in vivo assays, in contrast to their susceptible tva +/+ and tva +/- siblings. We also found a specific disorder of the cobalamin/vitamin B12 metabolism in the tva knock-out chickens, which is in accordance with the recently recognized physiological function of Tva as a receptor for cobalamin in complex with transcobalamin transporter. Last but not least, we bring a new example of the de novo resistance created by CRISPR/Cas9 editing of pathogen dependence genes in farm animals and, furthermore, a new example of gene editing in chicken.

• MeSH
• editace genu MeSH
• genový knockout MeSH
• kur domácí virologie   MeSH
• kuřecí embryo MeSH
• kyselina methylmalonová krev   MeSH
• posunová mutace MeSH
• ptačí proteiny genetika   fyziologie   MeSH
• virové receptory genetika   fyziologie   MeSH
• virus ptačí leukózy klasifikace   fyziologie   MeSH
• vitamin B 12 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Intragenic rearrangements and sequence variants in the calmodulin-binding transcription activator 1 gene (CAMTA1) can result in a spectrum of clinical presentations, most notably congenital ataxia with or without intellectual disability. We describe for the first time a myoclonic dystonia-predominant phenotype associated with a novel CAMTA1 sequence variant. Furthermore, by identifying an additional, recurrent CAMTA1 sequence variant in an individual with a more typical neurodevelopmental disease manifestation, we contribute to the elucidation of phenotypic variability associated with CAMTA1 gene mutations.

• MeSH
• dospělí MeSH
• dystonické poruchy genetika   MeSH
• fenotyp MeSH
• genetické asociační studie MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• nedoslýchavost genetika   MeSH
• nesmyslný kodon * MeSH
• poruchy zraku genetika   MeSH
• posunová mutace * MeSH
• předškolní dítě MeSH
• proteiny vázající vápník genetika   MeSH
• rodokmen MeSH
• sekvenční delece * MeSH
• sekvenování exomu MeSH
• trans-aktivátory genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

• MeSH
• buněčné klony MeSH
• buňky K562 MeSH
• CRISPR-Cas systémy MeSH
• genový knockout MeSH
• homozygot MeSH
• hyperhomocysteinemie farmakoterapie   genetika   MeSH
• kultivované buňky MeSH
• kyselina listová terapeutické užití   MeSH
• lidé MeSH
• megaloblastová anemie farmakoterapie   genetika   MeSH
• mladiství MeSH
• posunová mutace MeSH
• recidiva MeSH
• sekvenční delece MeSH
• sekvenování exomu MeSH
• sodíko-vodíkový výměnný transportér 1 nedostatek   genetika   MeSH
• vitamin B 12 terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Pathogenic sequence variants in the IQ motif- and Sec7 domain-containing protein 2 (IQSEC2) gene have been confirmed as causative in the aetiopathogenesis of neurodevelopmental disorders (intellectual disability, autism) and epilepsy. We report on a case of a family with three sons; two of them manifest delayed psychomotor development and epilepsy. Initially proband A was examined using a multistep molecular diagnostics algorithm, including karyotype and array-comparative genomic hybridization analysis, both with negative results. Therefore, probands A and B and their unaffected parents were enrolled for an analysis using targeted "next-generation" sequencing (NGS) with a gene panel ClearSeq Inherited DiseaseXT (Agilent Technologies) and verification analysis by Sanger sequencing. A novel frameshift variant in the X-linked IQSEC2 gene NM_001111125.2:c.1813_1814del, p.(Asp605Profs*3) on protein level, was identified in both affected probands and their asymptomatic mother, having skewed X chromosome inactivation (XCI) (100:0). As the IQSEC2 gene is a known gene escaping from XCI in humans, we expect the existence of mechanisms maintaining the normal or enough level of the IQSEC2 protein in the asymptomatic mother. Further analyses may help to the characterization of the presented novel frameshift variant in the IQSEC2 gene as well as to elucidate the mechanisms leading to the rare asymptomatic phenotypes in females.

• MeSH
• algoritmy MeSH
• delece genu MeSH
• dítě MeSH
• epilepsie komplikace   genetika   MeSH
• fenotyp MeSH
• genetická variace * MeSH
• inaktivace chromozomu X MeSH
• karyotypizace MeSH
• lidé MeSH
• neurovývojové poruchy komplikace   genetika   MeSH
• posunová mutace MeSH
• předškolní dítě MeSH
• pruhování chromozomů MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• srovnávací genomová hybridizace * MeSH
• výměnné faktory guaninnukleotidů genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

• MeSH
• benzamidy chemie   metabolismus   farmakologie   MeSH
• epitelové buňky cytologie   metabolismus   MeSH
• imidazolinové receptory antagonisté a inhibitory   genetika   metabolismus   MeSH
• indukované pluripotentní kmenové buňky cytologie   metabolismus   MeSH
• ledviny cytologie   metabolismus   patologie   MeSH
• lidé MeSH
• lyzozomy metabolismus   MeSH
• malá interferující RNA metabolismus   MeSH
• mucin 1 chemie   genetika   metabolismus   MeSH
• myši transgenní MeSH
• myši MeSH
• nemoci ledvin metabolismus   patologie   MeSH
• posunová mutace MeSH
• RNA interference MeSH
• signální dráha UPR účinky léků   MeSH
• transkripční faktor ATF6 metabolismus   MeSH
• vezikulární transportní proteiny chemie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

De novo sequence variants, including truncating and splicing variants, in the additional sex‑combs like 3 gene (ASXL3) have been described as the cause of Bainbridge‑Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi‑step molecular diagnostics algorithm, including karyotype and array‑comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next‑generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene‑rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.

• MeSH
• dítě MeSH
• lidé MeSH
• mikrocefalie genetika   MeSH
• pilotní projekty MeSH
• poruchy řeči genetika   MeSH
• posunová mutace MeSH
• rodokmen MeSH
• svalová hypotonie genetika   MeSH
• transkripční faktory genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.

• MeSH
• aktivační mutace genetika   MeSH
• cerebelární ataxie genetika   MeSH
• exom MeSH
• exony genetika   MeSH
• fenotyp MeSH
• hyperkineze genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mutace MeSH
• nesmyslný kodon genetika   MeSH
• posunová mutace genetika   MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 4 genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• sestřih RNA genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Recently, the genetic cause of several syndromic forms of glycemia dysregulation has been described. One of them, MEHMO syndrome, is a rare X-linked syndrome recently linked to the EIF2S3 gene mutations. MEHMO is characterized by Mental retardation, Epilepsy, Hypogonadism/hypogenitalism, Microcephaly, and Obesity. Moreover, patients with MEHMO had also diabetes and endocrine phenotype, but detailed information is missing. We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. Both probands had a neonatal hypoglycemia, early onset insulin-dependent diabetes, and hypopituitarism due to dysregulation and gradual decline of peptide hormone secretion. Based on the clinical course in our two probands and also in previously published patients, neonatal hypoglycemia followed by early-onset diabetes and hypopituitarism may be a consistent part of the MEHMO phenotype.

• MeSH
• diabetes mellitus 1. typu vrozené   genetika   MeSH
• endokrinní žlázy metabolismus   MeSH
• epilepsie genetika   MeSH
• eukaryotický iniciační faktor 2 genetika   MeSH
• fenotyp MeSH
• hypoglykemie vrozené   genetika   MeSH
• hypogonadismus genetika   MeSH
• hypopituitarismus vrozené   genetika   MeSH
• lidé MeSH
• mentální retardace vázaná na chromozom X genetika   MeSH
• mikrocefalie genetika   MeSH
• novorozenec MeSH
• obezita genetika   MeSH
• pohlavní orgány abnormality   MeSH
• posunová mutace MeSH
• transkripční faktory MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH

Chřipkové viry se vyskytují celosvětově. Ročně jimi onemocní v průměru 10 až 20 % populace. V důsledku toho zemře 250 000 až 500 000 pacientů ročně. Tato čísla by mohla být daleko nižší, kdyby lidé chřipkové infekce nepodceňovali a nezanedbávali prevenci. O to smutnější je fakt, že máme k dispozici vakcínu, tzn. vysoce účinný preventivní nástroj. Světová zdravotnická organizace (WHO) doporučuje 30% proočkovanost populace - Spojené státy dosahují podle CDC 46,8 % v rámci celé populace (nad šest měsíců věku), zatímco česká populace se pohybuje okolo pouhých 6 %. Alespoň částečnou odpověď na otázku, proč tomu tak je, se snaží nalézt následující text.

Influenza virus causes significant morbidity worldwide each year; ten to twenty percent people are infected. Based on current estimates, the influenza associated deaths range between 250,000 to 500,000 annually. Many of these preventable influenza-associated deaths result from underestimation of the influenza infection and common misconceptions about the benefits of the most effective method for influenza prevention - the influenza vaccine. WHO recommends 30% vaccination coverage. While in the United States of America the vaccination coverage reaches 46,8 % of population, in the Czech Republic the immunization coverage reaches only six percent of the population. The following commentary may provide some answers.

• MeSH
• chřipka lidská * patologie   terapie   virologie   MeSH
• epidemie MeSH
• genetický drift MeSH
• infekce viry z čeledi Orthomyxoviridae * komplikace   patologie   prevence a kontrola   MeSH
• lidé MeSH
• odmítnutí očkování MeSH
• Orthomyxoviridae * genetika   klasifikace   patogenita   MeSH
• pacientův souhlas se zdravotní péčí MeSH
• pandemie MeSH
• podpora zdraví MeSH
• posunová mutace MeSH
• rizikové faktory MeSH
• vakcíny proti chřipce * ekonomika   klasifikace   terapeutické užití   MeSH
• zdravotnický personál MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH
• Geografické názvy
• Česká republika MeSH
• Spojené státy americké MeSH