Новая мутация в гене TRIP4, ассоциированная с фенотипом врожденной мышечной дистрофии типа Давиньон–Шове (клинический случай)

Congenital muscular dystrophies are heterogeneous groups of neuromuscular diseases leading to hypotonia, progressive muscle weakness and dystrophic or structural signs in muscle biopsy. At the present time, 34 genes associated with congenital muscular dystrophy have been described. The clinical case of a rare form of congenital muscular dystrophia associated with a homozygous mutation in the TRIP4 gene in a patient with respiratory failure requiring respiratory support, neurological symptoms, muscular hypotonia, and multiple congenital malformations of skeletal system is presented for the first time in Russia. The undescribed pathogenic homozygous variant of the nucleotide sequence in the TRIP4 gene (chr15:64686179, c.136C>T, p.Arg46Ter, 2 exon, NM_016213.4) was detected by whole exome sequencing. The mutation in the TRIP4 gene was validated by Sanger sequencing in a child and its origin was investigated. The mother and father of the girl are carriers of the heterozygous variant in the TRIP4 gene. Identification of the genetic cause of a rare form of neuromuscular disease is important for determining the tactics of patient management and medical and genetic counseling of the family, as well as clarifying the pathogenesis of a rare pathology. Врожденные мышечные дистрофии и врожденные миопатии представляют собой гетерогенную группу нервно-мышечных заболеваний, приводящих к гипотонии, прогрессирующей мышечной слабости и дистрофическим или структурным признакам при мышечной биопсии. В настоящее время описано 34 гена, связанных с врожденной мышечной дистрофией. Впервые в России представляется клинический случай редкой формы врожденной мышечной дистрофии, обусловленной гомозиготной мутацией в гене TRIP4, у пациента с дыхательной недостаточностью, требующей респираторной поддержки, неврологической симптоматикой, мышечной гипотонией, множественными врожденными пороками развития опорно-двигательной системы. В результате проведенного полноэкзомного секвенирования выявлен ранее не описанный патогенный вариант нуклеотидной последовательности в гене TRIP4 в гомозиготном состоянии, приводящий к остановке синтеза полнофункционального белка (chr15:64686179, c.136C>T, p.Arg46Ter, 2 й экзон, NM_016213.4). Мутация в гене TRIP4 была валидирована методом секвенирования по Сэнгеру у ребенка, и исследовано ее происхождение. Мать и отец девочки являются носителями гетерозиготного варианта в гене TRIP4. Выявление генетической причины редкой формы нервно-мышечного заболевания важно для определения тактики ведения пациента и медико-генетического консультирования семьи, а также уточнения патогенеза редкой патологии

Assessment of “Specific Safety” Index of the Live Tularemia Vaccine

Analyzed were the results of specific safety control of the live tularemia dry vaccine used for tularemia prophylaxis. During the period of 1997-2006 this index was shown to be unstable. Specific safety of the vaccine is one of the main parameters of its quality, and in cases it does not meet the requirements of the normative documentation (ND) the vaccine is rejected during the control. It was proposed to introduce amendments in ND and to use for vaccine control standard animals, the conditions of their keeping being strictly observed

Features of the Biotopic Distribution of Different Species of Small Mammals and their Role in Supporting the Natural Foci of Tularemia in the North-Eastern Part of the Voronezh Region

Different species of small mammals (SM) (539 total), cached in Voronezh region, were examined for antigen and DNA of Francisella tularensis. The basic species of SM involved in circulation of F. tularensis were revealed. The features of the biotopic distribution of infected SM on the territory of the natural foci were shown. The diversity of species SM ensures long operation and epizootic activity of the natural foci of tularemia

Mutation of the ALDH7A1 gene in a patient with pyridoxal phosphate-dependent neonatal epileptic encephalopathy: a clinical case

The article presents a clinical case of severe infantile generalized idiopathic epilepsy with status-like seizures, muscular dystonia and developmental delay. The examination included a phenotypic analysis: the course of the perinatal period, the nature of seizures, cognitive and behavioral disorders; video electroencephalography, and brain MRI. Using the targeted exome sequencing of genes associated with epileptic encephalopathy (NGS), we detected a nucleotide heterozygous variant of the ALDH7A1 gene (previously not described). This mutation led to the appearance of a stop codon in position 82 of the protein p.Arg82Ter and the amino acid substitution in position 399 of the protein p.Glu399Gln. This clinical observation demonstrates the importance of DNA-based diagnosis involving the targeted exome sequencing to identify molecular defects, especially in severe neonatal drug-resistant seizures. In the case of confirmed mutations in the ALDH7A1 gene, the patient should be given vitamin B6 at the therapeutic doses for seizure relief

THE GENETIC SUSCEPTIBILITY TO ATHEROSCLEROSIS

Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Atherosclerosis is the main cause of death and disability in developed countries, while in developing countries the incidence of this pathology is growing rapidly. Advances in techniques of molecular genetics have revealed that genetic polymorphisms significantly influence susceptibility to atherosclerotic vascular diseases. A large number of candidate genes, genetic polymorphisms and susceptibility loci associated with atherosclerotic diseases have been identified in recent years and their number is rapidly increasing. In recent years, there is significant interest in identifying additional factors of genetic risk for atherosclerosis. In recent years, a large number of genetic studies have been carried out to prove the genetic effect on the atherosclerotic process. Rapid progress in the sequencing of the human genome and molecular genetic methods have helped in the definition of susceptibility loci and associated candidate genes with atherosclerosis and concomitant diseases. The association of a large number of susceptibility genes with atherosclerosis reflects the enormous complexity of the disease. Multiple factors, including endothelial dysfunction, lipid metabolism defects, inflammation and immune responses, oxidative stress, cell proliferation, tissue remodeling and hemostatic defects are involved in the pathogenesis of atherosclerosis. In this review we focus and discuss on some of the major candidate genes and genetic polymorphisms associated with human atherosclerotic vascular diseases

Helsmoortel-van der Aa syndrome syndrome in a patient with epilepsy, developmental delay, intellectual disability, and autism spectrum disorder

Autism spectrum disorders (ASDs) are a group of complex disintegrative disorders of mental development, characterized by a lack of ability to social interaction, communication, stereotyped behavior, leading to social maladaptation. We present a rare clinical case of a delay in psychomotor and speech development, specific facial dysmorphia, impaired behavior, and a detected mutation in the ADNP gene. When conducting targeted exomic sequencing, we revealed a previously undescribed variant of the nucleotide sequence in the ADNP gene (p.Ala1017fs). Mutations in the ADNP gene in a heterozygous state were described for patients with Helsmoortel-van der Aa syndrome (OMIM: # 615873). Mutations in the ADNP gene are the genetic cause of ASD in 0.17% of cases. When interpreting the data of new generation sequencing (NGS) in patients with epileptic encephalopathy, ASD, and characteristic phenotype, it is advisable to take into account that the ADNP gene is one of the key genes responsible for embryonic neurodevelopment

Pediatric encephalopathy: cinical, biochemical and cellular insights into the role of Gln52 of GNAO1 and GNAI1 for the dominant disease

Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1