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Some problems of molecular genetics are considered. A special attention is paied to enzymology of genetic processes, in particular, to the mechanism of DNA replication, gene ingeneering and the structure and activity regulation mechanisms of genetic loci in higher organisms.
This is a review of the properties and molecular genetics of six lysosomal hydrolases: beta-galactosidase, hexosaminidases A and B, alpha-galactosidase, beta-glucosidase and alpha-fucosidase. Each enzyme is discussed with regards to isoenzymes and substrate specificity, subunit structure, genetic relationship of isoenzymes and genetic variants. The molecular genetics of human diseases caused by deficiencies of each enzyme are discussed.
The molecular genetics of GM1 beta-galactosidase is reviewed. This enzyme exists in two forms, A and B. Form A is monomeric with a molecular weight of 72,000 and appears to be coded by a single autosomal locus. Form B is polymeric and cross-reacts with anti-A antibodies; it is coded wholly or in part by the same locus that codes for A. The simultaneous loss of A and B in GM1 gangliosidosis is explained. None of the other beta-galactosidases, including neutral beta-galactosidase, ceramide lactoside beta-galactosidase or cerebroside beta-galactosidase cross-react with anti-A antibodies, demonstrating that they are coded by loci separate from A. GM1 beta-galactosidase A is heterocatalytic, cleaving beta-D-galactose from ganglioside GM1, lactose, N-acetyllactosamine, and galactose-containing glycoproteins such as asialofetuin, red cell stromal glycoproteins and keratan sulfate. The pleotropic effects of a single mutation affecting the locus for beta-galactosidase A can be explained by a one gene:one polypeptide:many substrates model. Phenotypic variability among beta-galactosidase A mutants may result from better residual activity of the mutant enzyme for one substrate than for another. Patients with normal intelligence and severe bony deformities, who are homozygous for a mutation affecting the enzyme, illustrate this point. Thus far all human mutants for GM1 beta-galactosidase studied are structural mutants, synthesizing nearly normal quantities of mutant enzyme; one is a proven Km mutant, the others are very likely so.
OBJECTIVES: Disorders of sex development (DSD) include a range of conditions in which chromosomal, gonadal, or anatomical sex deviates from the typical developmental pathway. The diagnostic approach to DSD has shifted from karyotyping to molecular genetic tools. This study evaluated the clinical presentation, cytogenetic spectrum, and diagnostic utility of conventional and advanced molecular genetic investigations in patients with suspected DSD managed at a tertiary care facility in Eastern India over a three-year period. METHODS: A retrospective observational study was conducted at the Genetics Laboratory of a tertiary care teaching hospital in Eastern India. Consecutive patients with clinically suspected DSD referred between January 2022 and December 2024 were included. Demographic and clinical data were obtained from referral records, and peripheral blood samples were analysed using standard G-banded karyotyping according to the International System for Human Cytogenomic Nomenclature (ISCN 2020). Fluorescence in situ hybridisation (FISH), chromosomal microarray analysis (CMA), and whole-genome sequencing (WGS) were selectively performed in cases with inconclusive cytogenetic findings, suspected structural chromosomal abnormalities, or complex phenotypes. RESULTS: A total of 98 suspected DSD cases were evaluated during the study period. The most frequent chromosomal constitution was 46,XY DSD (37, 37.8%), followed by 46,XX DSD (30, 30.6%) and sex chromosome DSD (21, 21.4%). Culture failure occurred in 10 (10.2%) samples. Advanced genetic techniques, including FISH, CMA, and WGS, improved diagnostic clarification in selected complex cases. CONCLUSION: This experience highlights the importance of integrating contemporary high-resolution technologies with conventional cytogenetics to enhance the assessment, counselling, and treatment of individuals with DSD.
BACKGROUND: Hidradenitis suppurativa (HS) is a common, chronic and debilitating inflammatory disease that most commonly affects intertriginous skin. Despite its high heritability, the genetic underpinnings of HS remain poorly understood. OBJECTIVES: To identify genetic signals associated with HS, determine genetic relationships with other diseases and investigate potential molecular genetic mechanisms. METHODS: We performed a genome-wide association meta-analysis of six studies, totalling 4540 patients with HS and > 1 million control participants, and identified genetic correlations with other common diseases. We integrated the HS data with expression quantitative trait loci from 10 trait-relevant tissues, epigenomic and transcriptomic data from human scalp, differential expression data from HS lesions vs. adjacent skin and mesenchymal Hi-C chromatin looping data. To identify functional noncoding variants, we performed transcriptional reporter assays for signals near KLF5 and SOX9. RESULTS: We identified 11 significant HS signals across 7 loci: 4 corresponded to previously reported associations, 4 represented novel signals within known loci and 3 were signals in newly implicated loci. We identified significant genetic correlations between HS and other inflammatory conditions, particularly inflammatory bowel disease, rheumatoid arthritis, type 2 diabetes mellitus and asthma. We prioritized candidate genes for the 11 signals. The risk allele at KLF5 exhibited 10-fold greater transcriptional activity than the nonrisk allele, while risk alleles at SOX9 showed significantly reduced transcriptional activity. CONCLUSIONS: Our results provide insights into potential genetic mechanisms underlying HS and suggest potential therapeutic targets for this challenging condition.
The author considers the possibilities and limits of extrapolation of the data by the genetics of one species of bacteria to the other. It is emphasized that even in the related bacterial species a similar localization on chromosomes was inherent only to some of the unitypical genes, by in this case as well not all the genes were grouped in the same way, and differed by their delicate structure. An idea on the significant role of genetic metabolism in the microbial evolution is being developed; particular significance is attributed to plasmides. It is supposed that foreign plasmides, particularly transmissive factors of multiple drug resistance could aid in charting the chromosomes of bacteria in which the routes of transmission of genetic information are still unknown. A conclusion was drawn on the necessity of intensification and widening the investigations on the molecular genetics of bacteria of significance for public health and public economy.
Molecular analysis of normal and abnormal human globin genes and their gene products has recently provided information on the precise genetic events that result in hemoglobinopathies. In the case of structurally abnormal hemoglobins, the following mechanisms can be invoked: single nucleotide base substitutions leading to amino acid replacement or chain termination variants; nucleotide deletions (or additions) leading to deletion and frameshift variants; and nonhomologous crossing over leading to the production of fused globin chains. The molecular basis of the thalassemia syndromes, disorders characterized by absent or decreased synthesis of alpha- or beta-globin chains, is quite heterogeneous. In some cases globin gene deletions have been demonstrated; whereas in others there is probably either a defect in globin gene transcription or a defect in nuclear globin messenger RNA (mRNA) processing, mRNA transport or globin mRNA stability. In one form of beta(0)-thalassemia a nonsense mutation has recently been demonstrated, and other cases are also associated with some as yet undetermined functional abnormality of beta-globin mRNA.
The paper elucidates certain methodological problems of evolutionary histology. The principal attention is given to the necessary synthesis of modern molecular biology and genetics and evolutionary histology. Modern data on the levels of the organization of the living matter and their significance for the rightness of the A.A. Zavarzin's theory of parallel lines in the tissue evolution are presented. The hypothesis of an application of the theory of parallel lines in the hereditary variability by N.I. Vavilov to the analysis of regularities of the tissue evolution is set forth. The hypothesis is proposed that mutation changes of similar genes in representatives of different types of animals underlie the regularities of the tissue evolution discovered by A.A. Zavarzin, and epigenomic changes of regulation systems occurring most frequently in the process of ontogenesis of organisms lie in the basis of the divergent evolution of tissues after N.G. Chlopin.
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Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders characterised by skin fragility, caused by pathogenic variants in genes encoding structural components of the dermo-epidermal junction. With the advent of next-generation sequencing (NGS), the diagnostic paradigm has shifted from a morphological to a genotype-oriented approach. This review summarises the genetic architecture of EB, the types of mutations and genotype-phenotype relationships, the challenges in interpreting variants of unknown significance (VUS), and therapeutic strategies targeting specific mutational mechanisms, including read-through approaches, exon skipping and genome editing. The role of modifier genes and epigenetic factors in clinical variability is also discussed. The focus is on the translational potential of genomics for personalized therapy in EB. Overall, this review synthesizes the molecular basis of all four major EB types across 16+ classical genes, highlights the paradigm shift where NGS achieves a diagnostic yield exceeding 90%, and critically assesses recent therapeutic milestones-ranging from the first FDA-approved topical gene therapy to precision RNA and genome-editing modalities.
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Review of the data is presented on the hereditary disease gangliosidosis GM1 and on the enzyme beta-galactosidose, deficiency of which is responsible for this disease. Heterogeneity of the disease and existence of various forms of beta-galactosidase are considered. Possible correlation is discussed between the defects of the enzyme forms detected and the type of the disease.
We studied the effect of cadmium chloride on: (1) the DNA of human cells; (2) the mutagenic effect of reproducing Kilham virus; (3) the synthesis of virus-induced interferon, and (4) the reproduction of oncogenic (mammalian leucosis) virus. Cadmium chloride caused degradation of DNA in human- and rat-embryo cells. Culture infected by the virus in the presence of cadmium sulphate had the highest yield of cells with chromosomal aberrations. Cadmium chloride caused marked inhibition of the virus-induced synthesis of interferon. The introduction of cadmium chloride into diploid cells infected by the leucosis virus caused a 3-4 fold increase in the yield of virus-induced transformation foci.