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
- práce podpořená grantem MeSH
- Názvy látek
- NAV3 protein, human MeSH Prohlížeč
- proteiny asociované s mikrotubuly MeSH
- proteiny nervové tkáně 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.
- Klíčová slova
- Epilepsy, Neurodevelopmental disorder, SLC1A4, 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
- Názvy látek
- SLC1A4 protein, human MeSH Prohlížeč
- transportní systém ASC pro aminokyseliny 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
- Názvy látek
- EIF2S3 protein, human MeSH Prohlížeč
- eukaryotický iniciační faktor 2 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
- Názvy látek
- enzymy opravy DNA MeSH
- fosfotransferasy s alkoholovou skupinou jako akceptorem MeSH
- PNKP protein, human MeSH Prohlížeč
- protein XRCC1 MeSH
- XRCC1 protein, human MeSH Prohlížeč
- MeSH
- acidóza laktátová diagnóza genetika patologie MeSH
- exprese genu MeSH
- faciální stigmatizace MeSH
- fatální výsledek MeSH
- hypertrofická kardiomyopatie diagnóza genetika patologie MeSH
- hypospadie diagnóza genetika patologie MeSH
- lidé MeSH
- membránové proteiny nedostatek genetika MeSH
- mikrocefalie diagnóza genetika patologie MeSH
- mitochondriální proteiny nedostatek genetika MeSH
- mutace MeSH
- předškolní dítě MeSH
- svalová hypotonie diagnóza genetika patologie MeSH
- vrozená brániční kýla diagnostické zobrazování genetika patologie chirurgie MeSH
- vývojové poruchy u dětí diagnóza genetika patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- Publikační typ
- dopisy MeSH
- kazuistiky MeSH
- Názvy látek
- membránové proteiny MeSH
- mitochondriální proteiny MeSH
- TMEM70 protein, human MeSH Prohlížeč
The collections of the Museum in the Department of Anatomy, Faculty of Medicine, J. E. Purkynĕ University in Brno, include a skull of about 25 to 30-year-old individual with extreme microcephaly that has been so far described rarely in the morphological literature. The skull capacity is 355 cm3, which is only 26.1% of the skull capacity in a "normal" individual. While the facial skeleton is reduced only by 10-15% if compared with the norm, the cerebral part is striking by its extraordinarily small dimensions (smaller by 30-40% in comparison with the norm), particularly in the area of the frontal bone squama. The size of the skull is characterized best by the values of the basic metric measurements: maximal length of the skull 122 mm (norm: 172 mm), maximal breadth of the skull 94 mm (norm: 140 mm), height of the skull 96 mm (norm: 130 mm), circumference of the skull through the glabella 351 mm (norm: 510 mm). Foramen occipitale magnum is shifted strikingly to the dorsal direction. The cause of the microcephaly described cannot be explained explicitly just on the basis of the findings in the skull. For finding the actual cause a number of other data should be known. Authors' hypothesis that the problem is primary microcephaly has been supported even by roentgenological finding.
- MeSH
- epilepsie komplikace genetika MeSH
- kvadruplegie komplikace genetika MeSH
- lidé MeSH
- mikrocefalie komplikace genetika patologie MeSH
- předškolní dítě MeSH
- svalová spasticita komplikace genetika MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
