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At least 19 recordsLinked to original sources
PubMed1977

Glycosphingolipid hydrolases: properties and molecular genetics.

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.

Animals↗
PubMed2026

Three-Year Experience of Cytogenetic and Molecular Genetic Evaluation in Patients With Disorders of Sex Development at a Tertiary Care Centre in Eastern India.

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.

chromosomal analysis↗
PubMed2025

Genomic loci and molecular genetic mechanisms for hidradenitis suppurativa.

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.

Humans↗
PubMed1979

Molecular genetics of human hemoglobin synthesis.

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.

Amino Acid Sequence↗
PubMed2026

From the Microscope to the Genome: A New Era in the Molecular Genetics of Epidermolysis Bullosa.

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.

Humans↗
PubMedDate not supplied

[Lysosomal beta-galactosidase properties and the molecular genetics of GM1 gangliosidosis].

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.

Adult↗
PubMed1978

Molecular genetics of herpes simplex virus: demonstration of regions of obligatory and nonobligatory identity within diploid regions of the genome by sequence replacement and insertion.

The DNAs of herpes simplex virus (HSV) 1 and 2 consist of two components, L and S, each composed of unique sequences bracketed by inverted repeats. In this study we have probed the structure of the reiterated regions of the S component in marker rescue experiments involving transfection of cells with mixtures of intact HSV-1 mutant viral DNA and individual DNA fragments generated by restriction endonuclease digestion of wild-type HSV-1 or HSV-2 DNAs. The results were as follows: (i) HSV is diploid for the wild-type sequences that rescue two temperature-sensitive (ts) mutants. DNA fragments from both reiterated regions of the S component of HSV-1(F) DNA can rescue tsLB2 and tsD mutants. (ii) Identity of the entire reiterated sequence at both ends of S is not obligatory because only one end of the S component of wild phenotype virus HSV-1(1061) rescues tsD even though both ends rescue tsLB2. (iii) Genes in both reiterated sequences can be expressed. We produced, by marker rescue experiments, recombinants with heterotypic ends of the S component, and these specified corresponding polypeptides characteristic of both HSV-1 and HSV-2. (iv) The reiterated sequences of the S component may contain a region of obligatory identity. Thus, several recombinant clones produced by rescue with HSV-2 DNA contained identical HSV-2 DNA insertions within both reiterated regions of the HSV-1 S component. Consistent with this conclusion, the termini of the S component in the heterodiploids described in iii were identical by restriction enzyme analysis. (v) The observation that HSV DNA can be expanded by at least 5 x 10(6) by means of insertion in the S component suggests that it can be a vehicle for exogenous DNA.

Base Sequence↗
PubMed1979

Molecular genetics of herpes simplex virus: the terminal a sequences of the L and S components are obligatorily identical and constitute a part of a structural gene mapping predominantly in the S component.

In herpes simplex virus 1 (HSV-1) DNA, a small sequence, designated the a sequence, flanks the reiterated sequences at the ends of both the L and S components. The a sequence is the only sequence shared by the termini of all isomeric arrangements of HSV-1 DNA that arise from inversions of the covalently linked L and S components. We report that the a sequence, although present in both components, is a part of a structural gene mapping predominantly in the reiterated sequences of the S component. This conclusion is based on the observations that the mutant HSV-1(13)tsC75 is rescued by transfection of cells with the mutant DNA and any one of the four terminal or four L-S junction fragments of wild-type DNA. Furthermore, in doubly infected cells, this mutant shows little or no recombination or complementation with other ts mutants previously mapped within the reiterated sequences of the S component. Because it is otherwise difficult to explain the isolation of a mutant with several independent, equivalent mutations, the data argue for a mechanism that maintains the identity of the multiple copies of the a sequence.The paradox arising from the two observations that all termini rescue the ts mutant but that in coinfection tests the ts lesion is closely linked to the reiterated sequences of the S component could be accounted for by postulating that either recombination occurs while the DNA is in a circular form-in which case all a sequences would be adjacent to the reiterated sequence of the S component-or recombination can occur while the DNA is in a linear form. In this case the only effective substitution of the a sequence that is perpetuated is the one occurring at the L-S junction or in the S component. In light of the observations that tsC75 and the other mutants tested in this study map in the reiterated sequences and fail to yield appreciable recombinational frequencies, it is unlikely that isomerization of the DNA occurs by intramolecular recombination between reiterated sequences.

Base Sequence↗
PubMed1979

Molecular genetics of herpes simplex virus. II. Mapping of the major viral glycoproteins and of the genetic loci specifying the social behavior of infected cells.

We have mapped the location in herpes simplex virus (HSV) DNA of (i) three mutations at different loci (syn loci) which alter the social behavior of infected cells from clumping of rounded cells to polykaryocytosis, (ii) a mutation which determines the accumulation of one major glycoprotein [VP8.0(C(2))], and (iii) the sequences encoding four major virus glycoproteins [VP8.0(C(2)), VP7(B(2)), VP8.5(A), and VP19E(D(2))]. The experimental design and results were as follows. (i) Analysis of HSV-1 x HSV-2 recombinants showed that the sequences encoding the VP19E(D(2)) glycoprotein map in the S component, whereas the sequences encoding the other three major glycoproteins are in two locations in the L component of HSV DNA. The templates specifying the HSV-1 and HSV-2 glycoprotein VP8.0(C(2)) appear not to be colinear; we isolated recombinants specifying glycoproteins comigrating in sodium dodecyl sulfate-polyacrylamide gels with VP8.0(C(2)) of both HSV-1 and HSV-2. (ii) Marker rescue of a ts mutant defective in accumulation of glycoprotein VP7(B(2)) showed that the mutation maps within a region containing the sequences encoding that glycoprotein. (iii) Marker transfer experiments involving transfection of rabbit skin cells with donor HSV-1(F) DNA and fragments from several donor strains causing fusion of Vero or both Vero and HEp-2 cells revealed the existence of three syn loci specifying the social behavior of cells and one locus (Cr) determining the accumulation of glycoprotein VP8.0(C(2)). The Cr locus maps to the right of the template specifying VP8.0(C(2)) glycoprotein. Loci syn 1 and syn 2 map at or near the Cr locus but can be segregated from it. Locus syn 3 maps at or near the template specifying glycoproteins VP7(B(2)) and VP8.5(A). The expression of mutations in the syn 1 and syn 3 loci appear to be cell type dependent, in that recombinants with these mutations fuse Vero cells but not HEp-2 cells. Recipients of the syn 2 locus or of both syn 2 and syn 1 loci fuse both Vero and HEp-2 cells.

Animals↗