A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease

Purpose: The mediator (MED) multisubunit-complex modulates the activity of the transcriptional machinery, and genetic defects in different MED subunits (17, 20, 27) have been implicated in neurologic diseases. In this study, we identified a recurrent homozygous variant in MED11 (c.325C>T; p.Arg109Ter) in 7 affected individuals from 5 unrelated families. Methods: To investigate the genetic cause of the disease, exome or genome sequencing were performed in 5 unrelated families identified via different research networks and Matchmaker Exchange. Deep clinical and brain imaging evaluations were performed by clinical pediatric neurologists and neuroradiologists. The functional effect of the candidate variant on both MED11 RNA and protein was assessed using reverse transcriptase polymerase chain reaction and western blotting using fibroblast cell lines derived from 1 affected individual and controls and through computational approaches. Knockouts in zebrafish were generated using clustered regularly interspaced short palindromic repeats/Cas9. Results: The disease was characterized by microcephaly, profound neurodevelopmental impairment, exaggerated startle response, myoclonic seizures, progressive widespread neurodegeneration, and premature death. Functional studies on patient-derived fibroblasts did not show a loss of protein function but rather disruption of the C-terminal of MED11, likely impairing binding to other MED subunits. A zebrafish knockout model recapitulates key clinical phenotypes. Conclusion: Loss of the C-terminal of MED subunit 11 may affect its binding efficiency to other MED subunits, thus implicating the MED-complex stability in brain development and neurodegeneration

PDXK mutations cause polyneuropathy responsive to pyridoxal 5'-phosphate supplementation.

OBJECTIVE: To identify disease-causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. METHODS: We performed genome-wide sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery. We used circular dichroism to show secondary structure changes and isothermal titration calorimetry to investigate the impact of variants on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays and mass spectroscopy on recombinant protein, patient-derived fibroblasts, plasma, and erythrocytes. Response to supplementation was measured with clinical validated rating scales, electrophysiology, and biochemical quantification. RESULTS: We identified biallelic mutations in PDXK in 5 individuals from 2 unrelated families with primary axonal polyneuropathy and optic atrophy. The natural history of this disorder suggests that untreated, affected individuals become wheelchair-bound and blind. We identified conformational rearrangement in the mutant enzyme around the ATP-binding pocket. Low PDXK ATP binding resulted in decreased erythrocyte PDXK activity and low pyridoxal 5'-phosphate (PLP) concentrations. We rescued the clinical and biochemical profile with PLP supplementation in 1 family, improvement in power, pain, and fatigue contributing to patients regaining their ability to walk independently during the first year of PLP normalization. INTERPRETATION: We show that mutations in PDXK cause autosomal recessive axonal peripheral polyneuropathy leading to disease via reduced PDXK enzymatic activity and low PLP. We show that the biochemical profile can be rescued with PLP supplementation associated with clinical improvement. As B6 is a cofactor in diverse essential biological pathways, our findings may have direct implications for neuropathies of unknown etiology characterized by reduced PLP levels. ANN NEUROL 2019;86:225-240

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission

General trends of comparative linguistic cognitive science

© 2020, Universidad del Zulia. All rights reserved. The paper examines the main trends in the development of comparative linguistic, cognitive science; it analyzes the preconditions for the formation of this direction, and highlights the prospects and challenges for its further development. The authors emphasize that comparative linguo-cognitive studies open up new horizons for bilingual lexicography, in particular, to create a model of a new type dictionary. Active development of theoretical and methodological foundations of general and comparative linguistics, linguistic-cultural studies, pragmatic linguistics and linguistic didactics have formed a basis for the theoretical understanding of many provisions of cognitive linguistics

Presuppositions and shared knowledge in perception and production of business text

© 2019, Universidad del Zulia. All rights reserved. The study aims to investigate presuppositions and shared knowledge in perception and production of business text via comparative qualitative research methods. This study shows that in the perception and production of a business text in Kazakh, Russian and English, each business communicator has the sum of specific (communicative-pragmatic, encyclopaedic and linguistic) presuppositions and shared knowledge, which is characteristic of a given socio-professional and sociocultural context. In conclusion, a business specialist owns a set of professional and business skills, taken in a specific business context, which make this professional business community of communicants unique in their own way

Student as a personality: Dynamics of associative criteria

© BEIESP. This paper is devoted to the study of a student’s linguistic personality from the standpoint of the theory of linguistic-cultural types. The relevance of the study is due to the actively developing anthropological linguistics field of the theory of linguocultural type, within the framework of which generalized recognizable personalities as representatives of a certain linguistic culture are considered. The object under study is the conceptual characteristics and the resulting reactions to the stimulus word “student”. The purpose of this work is to linguistically represent a student as a person, to describe the notional component of the typified personality concept based on associative attributes. The paper proposes to expand the conceptual space of a character type by means of the associations obtained and to consider the character type of “student” as a person who is beyond the bounds of a cliche. The character type of student is a vivid representative of the sociocultural group, embodying the educational values of society. According to our observations, the description of the linguocultural character type of student through the eyes of students themselves gives a more detailed representation of the substantive component of the concept. The study is based on the associative and semantic field “student” which includes linguistic units reflecting the lexical-semantic space of student life; associated with the mental, emotional, physical, material, intellectual condition of a student; denoting character traits representing specific concepts/specific objects of the material world (educational supplies, a kind of instant food, etc.), etc

Practical tasks of studying literature in a foreign language and communication skills

© 2019, Universidad del Zulia. All rights reserved. The article is devoted to the methodology of teaching literature in a non-native language from the standpoint of developing students' skills of social experience via comparative qualitative research methods. As a result, the method of studying literature in a non-native language causes different types of differentiation of tasks according to the degree of complexity for different groups of students. In conclusion, in the Kazakh school, the dominant role of speaking determines the role of the receptive mechanism, the important role of changing the speaker and listener, the wide involvement of audio recordings

Practical tasks of studying literature in a foreign language and communication skills

© 2019, Universidad del Zulia. All rights reserved. The article is devoted to the methodology of teaching literature in a non-native language from the standpoint of developing students' skills of social experience via comparative qualitative research methods. As a result, the method of studying literature in a non-native language causes different types of differentiation of tasks according to the degree of complexity for different groups of students. In conclusion, in the Kazakh school, the dominant role of speaking determines the role of the receptive mechanism, the important role of changing the speaker and listener, the wide involvement of audio recordings