• MeSH
• lidé MeSH
• mikrocefalie * diagnóza   etiologie   patofyziologie   patologie   MeSH
• novorozenec MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

• MeSH
• Cercopithecus aethiops MeSH
• COS buňky MeSH
• dánio pruhované genetika   MeSH
• dítě MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mentální retardace * genetika   MeSH
• mikrocefalie * genetika   patologie   MeSH
• myši MeSH
• neurony metabolismus   patologie   MeSH
• předškolní dítě MeSH
• proteiny asociované s mikrotubuly genetika   metabolismus   MeSH
• proteiny nervové tkáně genetika   metabolismus   MeSH
• vývojové poruchy u dětí * genetika   MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nijmegenský zlomový syndróm je zriedkavo sa vyskytujúce závažné autozómovo recesívne dedičné ochorenie, patriace medzi vrodené imunodeficiencie spojené s chromozómovou instabilitou, s hypersenzitivitou k ionizujúcemu žiareniu, s vysokým a skorým výskytom malignít lymfoidného pôvodu. Charakteristickým znakom je mikrocefália s vtáčím vzhľadom tváre. Skoré stanovenie diagnózy je dôležité pre včasné zavedenie preventívnych opatrení, adekvátnu symptomatickú liečbu, skríning a terapiu komplikácií. Stanovenie T-cell receptor excision circles (TREC) pri novorodeneckom skríningu môže prispieť k jeho záchytu. Alogénna transplantácia hematopoetických kmeňových buniek vedie k úprave imunodeficitu a signifikantne zvyšuje dobu prežívania po prvej remisii hematologickej malignity. V slovanských populáciách sa vyskytuje 0,5–1 % heterozygótnych nosičov patogénnej mutácie NBN génu. Majú taktiež zvýšenú citlivosť k ionizujúcemu žiareniu a zvýšený výskyt malignít od stredného veku.

Nijmegen breakage syndrome is a rare autosomal recessive congenital disease that belongs to a group of inherited immunodeficiency diseases with chromosomal instability, hypersensitivity to ionizing radiation and high susceptibility to lymphoid malignancies at a young age. It is characterized by microcephaly with bird-like face appearance. Early diagnosis is important for quick introduction of preventive measures, appropriate symptomatic treatment, screening and treatment of complications. T-cell receptor excision circles (TREC) detection can be useful for diagnosis during neonatal screening. Allogeneic hematopoietic stem cell transplantation resolves immunodeficiency and improves the long term survival after first remission of hematological malignancy. There is 0,5–1% heterozygous carrier of pathogenic mutation in the NBN gene frequency among Slavs. They are hypersensitive to ionizing radiation too, with higher occurrence of malignities since middle age.

• Klíčová slova
• mutace NBN,
• MeSH
• chromozomální nestabilita genetika   MeSH
• hematologické nádory etiologie   genetika   klasifikace   MeSH
• lidé MeSH
• mikrocefalie etiologie   genetika   MeSH
• primární imunodeficience diagnóza   etiologie   komplikace   MeSH
• syndrom Nijmegen breakage * diagnóza   genetika   komplikace   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• hlava abnormality   MeSH
• lidé MeSH
• megalencefalie * diagnóza   etiologie   terapie   MeSH
• mikrocefalie * diagnóza   etiologie   terapie   MeSH
• nemoci novorozenců MeSH
• novorozenec MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• přehledy MeSH

Adenylosuccinate lyase (ADSL) functions in de novo purine synthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado, and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL-deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

• MeSH
• adenylsukcinátlyasa nedostatek   metabolismus   MeSH
• aminoimidazolkarboxamid analogy a deriváty   metabolismus   MeSH
• autistická porucha metabolismus   MeSH
• buněčné linie MeSH
• buněčný cyklus MeSH
• ciliopatie metabolismus   MeSH
• dánio pruhované metabolismus   MeSH
• fenotyp MeSH
• fosfoproteiny metabolismus   MeSH
• kur domácí metabolismus   MeSH
• lidé MeSH
• mikrocefalie metabolismus   MeSH
• neurogeneze * MeSH
• poruchy autistického spektra metabolismus   MeSH
• poruchy metabolismu purinů a pyrimidinů metabolismus   MeSH
• poškození DNA MeSH
• proteiny asociované s mikrotubuly metabolismus   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• puriny metabolismus   MeSH
• ribonukleotidy metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

INTRODUCTION: Biallelic variants in the SLC1A4 gene have been so far identified as a very rare cause of neurodevelopmental disorders with or without epilepsy and almost exclusively described in the Ashkenazi-Jewish population. PATIENTS AND METHODS: Here we present Czech patient with microcephaly, severe global developmental delay and intractable seizures whose condition remained undiagnosed despite access to clinical experience and standard diagnostic methods including examination with an epilepsy targeted NGS gene panel. RESULTS: Whole exome sequencing revealed a novel variant NM_003038.4:c.1370G > A p.(Arg457Gln) of the SLC1A4 gene in a homozygous state in the patient, and afterwards Sanger sequencing in both parents confirmed the biallelic origin of the variant. A variant in the same codon, but with a different amino acid exchange, was described previously in a patient that had a very similar phenotype, however, without epilepsy. CONCLUSION: Our data suggest that the SLC1A4 gene should be considered in the diagnosis of patients with severe, early onset neurodevelopmental impairment with epilepsy and encourage the analysis of SLC1A4 gene variants via targeted NGS gene panel or whole exome sequencing.

• MeSH
• dítě MeSH
• homozygot MeSH
• lidé MeSH
• mikrocefalie genetika   patologie   MeSH
• mutace MeSH
• neurovývojové poruchy genetika   patologie   MeSH
• transportní systém ASC pro aminokyseliny genetika   MeSH
• záchvaty genetika   patologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

MEHMO syndrome is a rare X-linked syndrome characterized by Mental retardation, Epilepsy, Hypogenitalism, Microcephaly, and Obesity associated with the defect of protein synthesis caused by the EIF2S3 gene mutations. We hypothesized that the defect in protein synthesis could have an impact on the immune system. We describe immunologic phenotype and possible treatment outcomes in patient with MEHMO syndrome carrying a frame-shift mutation (I465fs) in the EIF2S3 gene. The proband (currently 9-year-old boy) had normal IgG and IgM levels, but had frequent respiratory and urinary tract infections. On subcutaneous immunoglobulin therapy achieving supra-physiological IgG levels the frequency of infections significantly decreased in Poisson regression by 54.5 % (CI 33.2-89.7, p=0.017). The MEHMO patient had had frequent acute infections despite normal IgG and IgM serum levels and responded well to the immunoglobulin treatment.

• MeSH
• dítě MeSH
• epilepsie farmakoterapie   genetika   imunologie   patologie   MeSH
• eukaryotický iniciační faktor 2 genetika   MeSH
• fenotyp MeSH
• hypogonadismus farmakoterapie   genetika   imunologie   patologie   MeSH
• lidé MeSH
• mentální retardace vázaná na chromozom X farmakoterapie   genetika   imunologie   patologie   MeSH
• mikrocefalie farmakoterapie   genetika   imunologie   patologie   MeSH
• mutace * MeSH
• obezita farmakoterapie   genetika   imunologie   patologie   MeSH
• pohlavní orgány abnormality   imunologie   patologie   MeSH
• výsledek terapie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

• MeSH
• apraxie genetika   patologie   MeSH
• Charcotova-Marieova-Toothova nemoc genetika   patologie   MeSH
• dvouřetězcové zlomy DNA * MeSH
• enzymy opravy DNA genetika   MeSH
• fibroblasty metabolismus   patologie   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem genetika   MeSH
• jednořetězcové zlomy DNA * MeSH
• lidé MeSH
• mikrocefalie genetika   patologie   MeSH
• mutace genetika   MeSH
• oprava DNA genetika   MeSH
• protein XRCC1 genetika   MeSH
• záchvaty genetika   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The SLX4 tumor suppressor is a scaffold that plays a pivotal role in several aspects of genome protection, including homologous recombination, interstrand DNA crosslink repair and the maintenance of common fragile sites and telomeres. Here, we unravel an unexpected direct interaction between SLX4 and the DNA helicase RTEL1, which, until now, were viewed as having independent and antagonistic functions. We identify cancer and Hoyeraal-Hreidarsson syndrome-associated mutations in SLX4 and RTEL1, respectively, that abolish SLX4-RTEL1 complex formation. We show that both proteins are recruited to nascent DNA, tightly co-localize with active RNA pol II, and that SLX4, in complex with RTEL1, promotes FANCD2/RNA pol II co-localization. Importantly, disrupting the SLX4-RTEL1 interaction leads to DNA replication defects in unstressed cells, which are rescued by inhibiting transcription. Our data demonstrate that SLX4 and RTEL1 interact to prevent replication-transcription conflicts and provide evidence that this is independent of the nuclease scaffold function of SLX4.

• MeSH
• DNA-helikasy genetika   metabolismus   MeSH
• dyskeratosis congenita genetika   MeSH
• genetická transkripce * MeSH
• HeLa buňky MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mikrocefalie genetika   MeSH
• protein FANCD2 genetika   metabolismus   MeSH
• rekombinasy genetika   metabolismus   MeSH
• replikace DNA * MeSH
• růstová retardace plodu genetika   MeSH
• zárodečné mutace MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• neurokranium,
• MeSH
• anamnéza MeSH
• dítě MeSH
• hydrocefalus diagnostické zobrazování   patologie   MeSH
• kraniofaciální abnormality * klasifikace   patologie   MeSH
• lebka patologie   růst a vývoj   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• megalencefalie patologie   MeSH
• mikrocefalie klasifikace   patologie   MeSH
• mozek patologie   růst a vývoj   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• kazuistiky MeSH