SEARCH · PubMed Health

Results for “Structural variants”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources

PubMed2026

Signals of Natural Selection Across Regions of Low Recombination in Wild Populations of the Purple Sea Urchin, Strongylocentrotus purpuratus.

Structural variants (SVs) are increasingly recognized as important components of genetic architecture. Yet our understanding of the evolutionary forces maintaining SVs in natural populations is limited. Chromosomal inversions in particular can facilitate local adaptation in populations with high gene flow, including many marine species. The purple sea urchin (Strongylocentrotus purpuratus) is a powerful system to study these dynamics due to its high gene flow, lack of population structure, and broad latitudinal range. We analyzed whole genome sequence data from 137 individuals sampled across seven populations to identify regions of low recombination using scans for elevated linkage disequilibrium and genetic differentiation. Such regions may arise from structural variants, including chromosomal inversions. We identified nine regions showing signatures of reduced recombination, including three way genotype clustering, long range linkage, and hanging bridge patterns frequently associated with inversion polymorphisms. The regions were polymorphic within locations and along the species range with three loci showing concordant signatures of balancing and spatially heterogeneous selection based on enrichment of outliers and distinct patterns of allelic age. Additionally, these loci showed enrichment for genes associated with biomineralization and development. Our results provide the first evidence for regions of low recombination in the purple sea urchin genome, several of which display genomic signatures consistent with structural variants such as chromosomal inversions. These findings add to growing evidence that regions of reduced recombination constitute an important component of standing genetic variation in natural populations and may play a key role in adaptation to heterogeneous environments.

Strongylocentrotus purpuratus↗

PubMed2026

Long-read sequencing resolves complex CYP21A2 variants and identifies 2+0 carriers in 21-hydroxylase deficiency.

The complex CYP21A2 variants arising from high homology with its pseudogene CYP21A1P challenge the diagnosis of 21-hydroxylase deficiency (21-OHD). This study systematically evaluated long-read sequencing (LRS) for identifying complex structural variants of the CYP21A2 gene in 21-OHD in comparison with conventional molecular diagnostic methods, including multiplex ligation-dependent probe amplification (MLPA), CNVplex, and SNaPshot. Twenty patients with suspected 21-OHD and defined CYP21A2 structural variants identified via initial MLPA screening were enrolled. Variants were further analyzed using CNVplex and SNaPshot, then all samples underwent LRS for comprehensive variant detection, breakpoint mapping, and haplotype resolution. LRS overcame key limitations of conventional methods. It reliably identified a novel large-fragment deletion and defined its boundaries. Notably, LRS identified "2+0" carriers, where deletions masked by duplications cause false-negatives with standard techniques. Moreover, LRS accurately distinguished CYP21A1P/CYP21A2_CH-4 and CH-9 chimera subtypes which were indistinguishable by the combined conventional assays. Furthermore, LRS enabled the precise identification and characterization of TNXA/TNXB chimeric deletions. These are frequently misclassified as CYP21A1P/CYP21A2 chimeras by conventional methods but are critical for diagnosing associated conditions such as CAH-X syndrome. LRS provides a superior, integrated solution for the molecular diagnosis of 21-OHD, offering precise structural variant characterization, accurate carrier detection, and reliable breakpoint mapping. Its application enhances diagnostic accuracy, supports advanced genetic counseling, and paves the way for genotype-informed clinical management.

Journal Article↗

PubMed1993

Inside-out integrin signaling in macrophages. Analysis of the role of the alpha 6A beta 1 and alpha 6B beta 1 integrin variants in laminin adhesion by cDNA expression in an alpha 6 integrin-deficient macrophage cell line.

Leukocytes use the alpha 6 beta 1 integrin to adhere to laminin based on mAb inhibition and affinity chromatography studies. This adhesion requires leukocyte stimulation with either PMA or specific cytokines, a process that has been termed "inside-out" integrin signaling. In the present study, the involvement of alpha 6 integrin structural variants in this regulated adhesion was examined using mouse macrophages. The two known alpha 6 structural variants, alpha 6A and alpha 6B, differ only in their cytoplasmic domain sequences. Using reverse transcriptase-polymerase chain reaction, we observed that macrophages express only the alpha 6A structural variant, in contrast to most cell types which express both alpha 6A and alpha 6B variants. The role of this integrin subunit in macrophage adhesion was assessed by cDNA transfection of P388D1 cells. We found that this mouse macrophage cell line does not adhere to laminin even in response to phorbol 12-myristate 13-acetate (PMA) stimulation, though it does adhere normally to fibronectin and tissue culture plastic. Subsequent analysis employing reverse transcriptase-polymerase chain reaction and immunoprecipitation of surface labeled cells revealed that this cell line expresses neither the alpha 6A nor alpha 6B integrin subunits. Stable transfection of either the chick or human alpha 6A cDNAs into P388D1 cells resulted in chimeric alpha 6A beta 1 surface expression. The alpha 6A transfectants exhibited inside-out integrin signaling because PMA stimulation markedly increased their ability to adhere to laminin but it did not increase alpha 6A beta 1 surface expression. Similar results were obtained after transfection of the human alpha 6B cDNA. Analysis of the human transfectants was facilitated by the generation of a monoclonal antibody, 2B7, that is specific for the human alpha 6 integrin subunit. These observations demonstrate that both alpha 6A beta 1 and alpha 6B beta 1 can be regulated by inside-out signaling pathways in macrophages, even though this cell type expresses only alpha 6A beta 1. The data presented also demonstrate clearly that the alpha 6A and alpha 6B cytoplasmic domains do not differ in their ability to be regulated by PMA.

Amino Acid Sequence↗

PubMed1979

Carbohydrate of the human plasminogen variants. III. Structure of the O-glycosidically linked oligosaccharide unit.

The preceding two manuscripts in this issue (Hayes, M. L., and Castellino, F. J. (1979) J. Biol. Chem. 254, 8768-8771, 8772-8776) describe the isolation and characterization of glycopeptides from human plasminogen affinity chromatography variants 1 and 2. Plasminogen variant 1 contains an asparagine288-based branched carbohydrate structure, which has been established in the immediately preceding manuscript. This structure is absent in variant 2. Plasminogen variants 1 and 2 contain a threonine-based glycoconjugate. This latter structure has been established by combination of methylation data, glycosidase digestions, periodate oxidations, and Smith degradations of the beta-eliminated reduced oligosaccharides. One glycopeptide unit, isolated from both plasminogen variants 1 (1D) and 2 (2D) possessed the following structure: Sia alpha 2 yields 3Gal beta 1 yields 3GalNAc-Thr. The threonine was found to be residue 345 in the Glu-plasminogen sequence. Another glycopeptide unit was also found to be present, in lower yields in both variants 1 (1E) and 2 (2E). The structure of this unit was: Sia alpha 2 yields 3Gal beta1 yields 3GalNAc-Thr. : formula: (see text), alpha 2,6 Sia. Again Thr 345 was the glycosylated amino acid. The amino acid sequence around the glycosylated threonine was found to be NH2-Ala.Pro.Thr(CHO).Ala.Pro.Pro.Glu.

Amino Acid Sequence↗

PubMed1995

A multiple site-specific DNA-inversion model for the control of Omp1 phase and antigenic variation in Dichelobacter nodosus.

The molecular cloning and sequence analysis of four structurally variant linked genes (omp1A,B,C,D) that encode the major outer membrane protein of Dichelobacter nodosus strain VCS1001 are described. The isolation of rearranged copies of omp1A and omp1B, and the identification in the 5' regions of all four genes of short cross-over-site sequences that were similar to the Din family of cross-over-site sequences, suggested that site-specific DNA inversion was involved in omp1 rearrangement. Evidence for site-specific inversion of the 497 bp DNA fragment, which was located between the divergently orientated omp1A and omp1B genes, and which contained the promoter and 5' coding sequence of Omp1, was obtained by polymerase chain reaction-mediated amplification of inverted forms of these genes. However, to account for all of the omp1 gene copies cloned in this study, a more widespread inversion phenomenon must be involved in the rearrangement of these genes and a model for multiple site-specific DNA inversions at the omp1 locus is described. In this model the four structurally variant omp1 genes can be assembled from one of four structurally variant C-terminal coding regions and a conserved N-terminal coding region and can be expressed from a single promoter. It is postulated that this genetic capability endows D. nodosus with the ability to switch the antigenic specificity of one of its major surface proteins.

Amino Acid Sequence↗

PubMed2025

Whole-genome sequencing, as a powerful diagnostic tool in hearing loss, reveals novel variants in PTPRQ missed by whole-exome sequencing.

BACKGROUND/OBJECTIVES: Hearing loss (HL) is one of the most common congenital disorders, affecting 1-2 in 1,000 newborns. Modern genetic diagnostics using large gene panels and/or whole exome analysis (WES) can identify disease-causing mutations in 25-50 % of patients, with higher solve rates in individuals with earlier onset. RESULTS: Here, we used whole-genome sequencing (WGS) to reanalyze 14 index patients/families who remained without genetic diagnosis by WES. We were able to identify the genetic cause of HL in 6 families (43 %). Two families were diagnosed with DFNB84A caused by compound heterozygous recessive mutations in PTPRQ. Three of the four underlying variants, including a structural variant, a deep intronic variant, and a splice variant, escaped detection by WES. Minigene assays confirmed the pathogenicity of the intronic and the splice variants. In addition, we used protein 3D structure prediction and rigid ligand docking to study the pathogenicity of variants that escape nonsense-mediated decay. CONCLUSION: In our study, we present four novel variants in PTPRQ, three of which were detected only by WGS. To our knowledge, we report here the first pathogenic deep intronic PTPRQ variant causing HL. Our results suggest that the mutational spectrum of PTPRQ is not well covered by standard WES and that PTPRQ-associated hearing loss may be more frequent than previously thought. WGS provides an additional layer of information in the diagnostics of HL.

Humans↗

PubMed1994

Biological activities and secondary structures of variant forms of human salivary cystatin SN produced in Escherichia coli.

Using an Escherichia coli expression system, pGEX-2T, that expresses foreign sequences as fusion proteins with a glutathione S-transferase (GST) carrier, we have produced several recombinant human salivary cystatin SN (reCsnSN) variants. These include a N-terminal-truncated form (aa 17-121), a C-terminal-truncated form (aa 1-102) and two deletion mutants (delta 12-16 and delta 56-60). A large amount of the insoluble fusion protein (approx. 15 mg/l) was produced in each case. These were solubilized with urea and refolded by dialysis. The GST carrier was then cleaved with thrombin and the reCsn variants (except delta 56-60) were purified by anion-exchange chromatography. The CysP inhibitory activities against papain, and bovine and human cathepsin B, and secondary structures of the reCsnSN variants were determined and compared to natural salivary CsnSN. The full-length reCsnSN, the N-truncated and the delta 12-16 variants inhibited the CysP activity of papain and displayed circular dichroism (CD) spectra similar to that of natural CsnSN. On the other hand, the delta 56-60 mutant and the C-truncated variant exhibited very little inhibitory activity towards papain. The CD spectrum of the C-truncated variant indicated a change in the secondary structure (e.g., a decrease in beta-sheet and an increase of an alpha-helical content). Neither, the natural nor the full-length reCsnSN or the delta 12-16 mutant exhibited any inhibitory activity towards bovine and human cathepsin B.

Amino Acid Sequence↗

PubMed2026

Small Copy Number Neutral Intrachromosomal Translocation of PAX6 and Aniridia.

IMPORTANCE: Approximately 5% to 10% of individuals with classic aniridia do not receive a molecular diagnosis after clinical testing for variants in PAX6 and its downstream regulatory region. OBJECTIVE: To apply optical genome mapping (OGM) and long-read whole-genome sequencing (lrWGS) to diagnose an individual with unexplained classic aniridia. DESIGN, SETTING, AND PARTICIPANTS: High-quality DNA was extracted from the blood of a 16-year-old male patient with classic aniridia and prior negative clinical test results that included sequencing and copy number analysis of PAX6 exons and downstream regulatory region as well as genomic analysis via short-read whole-genome sequencing (srWGS) and analyzed using OGM and lrWGS. All analyses were performed in a research laboratory in Wisconsin from January 2019 to September 2025. INTERVENTIONS: OGM and lrWGS. MAIN OUTCOMES AND MEASURES: Identification of a structural variant disrupting PAX6 expression in an individual with classic aniridia, following negative prior testing including srWGS. RESULTS: OGM identified a 55-kb deletion on 11p13 encompassing all PAX6 exons and exon 12 of ELP4, with insertion of this segment into 11q21. lrWGS delineated the exact breakpoints, confirming that the downstream regulatory region, required for normal PAX6 expression, remained at the 11p13 locus. Consequently, the translocated copy of PAX6 at 11q21 is expected to lack expression due to the loss of its essential regulatory elements. CONCLUSIONS AND RELEVANCE: These findings in an individual with classic aniridia harboring an intrachromosomal rearrangement at the PAX6 locus identified by OGM and lrWGS may represent the smallest reported structural variant to separate the PAX6 coding sequence from its downstream regulatory region. This structural variant may have fallen below the detection threshold of srWGS due to its balanced nature and small size, suggesting OGM and lrWGS would be needed for definitive identification.

Aniridia↗

PubMed1981

Inhibitor studies of phage T4 wild-type and mutant DNA polymerases. V. A. summary of kinetic and inhibitor data.

The DNA polymerases of phage T4 wild-type, the mutator mutant L98 and the antimutator mutant CB121 were purified about 100-fold free of foreign enzyme activities interfering with the polymerase assay. The enzymes were characterized as to thermostability, exonuclease activity and kinetic data with DNA template primer, deoxythymidine 5' -triphosphate, and a mixture of all four deoxynucleoside 5' -triphosphates. The effects of eight inhibitors of DNA synthesis on the three enzymes were determined (Schroeder and Jantschak 1978 and 1980, Jantschak and Schroeder 1980) and are compared here. The most selective inhibitor, pyridoxal 5' -phosphate, interacts with the active site of the polymerases while the two least discriminating drugs, distamycin A and actinomycin D, do not directly interact with the polymerases at all. The study was intended to test whether specific enzyme inhibitors elicit a differential response in temperature-sensitive structural variants of this enzyme and whether, in principle, structural variants of virus enzymes or the respective ts- mutants in vivo are suitable as a screening system for selective antiviral agents.

DNA-Directed DNA Polymerase↗

PubMed1991

Secretion and in vivo folding of the Fab fragment of the antibody McPC603 in Escherichia coli: influence of disulphides and cis-prolines.

Using the well-characterized antibody McPC603 as a model, we had found that the Fv fragment can be isolated from Escherichia coli as a functional protein in good yields, whereas the amount of the correctly folded Fab fragment of the same antibody produced under identical conditions is significantly lower. In this paper, we analyse the reasons for this difference. We found that a variety of signal sequences function in the secretion of the isolated chains of the Fab fragment or in the co-secretion of both chains in E.coli. The low yield of functional Fab fragment is not caused by inefficient expression or secretion in E.coli, but by inefficient folding and/or assembly in the periplasm. We compared the folding yields for the Fv and the Fab fragment in the periplasm under various conditions. Several diagnostic framework variants were constructed and their folding yields measured. The results show that substitutions affecting cis-proline residues and those affecting various disulphide bonds in the protein are by themselves insufficient to dramatically change the partitioning of the folding pathway to the native structure, and the cause must lie in a facile aggregation of folding intermediates common to all structural variants. However, all structural variants could be obtained in native form, demonstrating the general utility of the secretory expression strategy.

Amino Acid Sequence↗

PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗

PubMed1980

Inherited structural polymorphism of the fourth component of human complement.

Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.

Alleles↗

PubMed1997

Properties of intraepithelial neoplasia relevant to the development of cancer chemopreventive agents.

Cancer chemoprevention is concerned with the development of drugs or diet supplements that will avert the onset or stop the progression of the intraepithelial neoplasia which precedes invasive cancer. Two basic processes underlie the onset and development of intraepithelial neoplasia. First is genomic instability (often associated with chronic diffuse epithelial hyperplasia), which is the increased production of genomic structural variants due to unrepaired DNA breaks with secondary formation of abnormal structures, including "mutator" mutations in genes responsible for genomic stability, gene copy amplification or loss from DNA breakage-fusion-anaphase bridge cycles, unequal sister chromatid exchange, and accumulation of double minutes. Second is the development within an epithelium having genomic instability of multicentric neoplastic lesions that independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (1) early diagnosis and treatment of genomic instability before the appearance of intraepithelial neoplasia, i.e., during the "predysplastic" or "premorphologic" phase, (2) development of multiple agents that block intralesional proliferation at steps along the "command" pathways of mitotic signal transduction and along the "execute" pathways of synthesis of daughter cell components, (3) development of nontoxic antiinflammatory agents, antioxidants, antimutagens, and proapoptotics, (4) avoidance of "clonal escape" through use of drug combinations, and (5) use of computer-assisted quantitative image analysis to assay modulation of surrogate endpoints in chemoprevention clinical trials.

Carcinoma in Situ↗

PubMed2000

New insights into the thyroid-stimulating hormone receptor. The major antigen of Graves' disease.

The receptor for thyroid-stimulating hormone is one of the most interesting hormone-binding sites because of its close association with common human diseases, including thyroid nodules and Graves' hyperthyroidism. This article discusses the structure and biosynthetic processing of this elusive glycoprotein, whose paucity and instability have impeded its isolation from natural sources. Topics include cleavage and subunit structure, variant species, and structural modeling, the thyroid-stimulating hormone receptor as the major autoantigen in Graves' disease, and a summary of recent efforts to replicate the symptoms of this uniquely human disease in animal models.

Alternative Splicing↗

PubMed1998

Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects.

Detailed structural and functional studies over the last decade have led to current recognition of the mycobacterial lipoarabinomannan (LAM) as a phosphatidylinositol anchored lipoglycan with diverse biological activities. Fatty acylation has been demonstrated to be essential for LAM to maintain its functional integrity although the focus has largely been on the arabinan motifs and the terminal capping function. It has recently been shown that the mannose caps may be involved not only in attenuating host immune response, but also in mediating the binding of mycobacteria to and subsequent entry into macrophages. This may further be linked to an intracellular trafficking pathway through which LAM is thought to be presented by CD1 to subsets of T-cells. The implication of LAM as major histocompatibility complex (MHC)-independent T-cell epitope and the ensuing immune response is an area of intensive studies. Another recent focus of research is the biosynthesis of arabinan which has been shown to be inhibitable by the anti-tuberculosis drug, ethambutol. The phenomenon of truncated LAM as synthesized by ethambutol resistant strains provides an invaluable handle for dissecting the array of arabinosyltransferases involved, as well as generating much needed structural variants for further structural and functional studies. It is hoped that with more systematic investigations based on clinical isolates and human cell lines, the true significance of LAM in the immunopathogenesis of tuberculosis and leprosy can eventually be explained.

Animals↗

PubMed1998

High-resolution structures of variant Zif268-DNA complexes: implications for understanding zinc finger-DNA recognition.

BACKGROUND: Zinc fingers of the Cys2-His2 class comprise one of the largest families of eukaryotic DNA-binding motifs and recognize a diverse set of DNA sequences. These proteins have a relatively simple modular structure and key base contacts are typically made by a few residues from each finger. These features make the zinc finger motif an attractive system for designing novel DNA-binding proteins and for exploring fundamental principles of protein-DNA recognition. RESULTS: Here we report the X-ray crystal structures of zinc finger-DNA complexes involving three variants of Zif268, with multiple changes in the recognition helix of finger one. We describe the structure of each of these three-finger peptides bound to its corresponding target site. To help elucidate the differential basis for site-specific recognition, the structures of four other complexes containing various combinations of these peptides with alternative binding sites have also been determined. CONCLUSIONS: The protein-DNA contacts observed in these complexes reveal the basis for the specificity demonstrated by these Zif268 variants. Many, but not all, of the contacts can be rationalized in terms of a recognition code, but the predictive value of such a code is limited. The structures illustrate how modest changes in the docking arrangement accommodate the new sidechain-base and sidechain-phosphate interactions. Such adaptations help explain the versatility of naturally occurring zinc finger proteins and their utility in design.

Amino Acid Sequence↗

PubMed1980

Structure of a newly isolated variant of Simian virus 40 DNA containing monkey DNA and its similarity to previously isolated variants.

The structure of a newly and independently isolated defective variant of simian virus 40 that contains covalently linked monkey and SV40 DNA sequences is described. This variant, termed 290, has a structure essentially identical with a previously isolated and characterized variant named CVP8/1/P2 (Eco RI res). The structural similarities include the monkey (host) DNA segment that is combined with viral DNA sequences, the particular viral DNA segment that is present, and the arrangement of these within the defective genome. The monkey DNA segment contains sequences derived from both low and high reiteration frequency monkey DNA. The viral sequences include the origin of replication. The separate isolation of essentially identical variants suggests a high level of specificity in the events leading to the formation and amplification of this type of defective genome.

Animals↗

PubMed1990

A new member of a secretory protein gene family in the dipteran Chironomus tentans has a variant repeat structure.

We describe the structure of a gene expressed in the salivary gland cells of the dipteran Chironomus tentans and show that it encodes 1 of the approximately 15 secretory proteins exported by the gland cells. This sp115,140 gene consists of approximately 65 copies of a 42-bp sequence in a central uninterrupted core block, surrounded by short nonrepetitive regions. The repeats within the gene are highly similar to each other, but divergent repeats are present in a pattern which suggests that the repeat structure has been remodeled during evolution. The 42-bp repeat in the gene is a simple variant of the more complex repeat unit present in the Balbiani ring genes, encoding four of the other secretory proteins. The structure of the sp115,140 gene suggests that related repeat structures have evolved from a common origin and resulted in the set of genes whose secretory proteins interact in the assembly of the secreted protein fibers.

Amino Acid Sequence↗