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PubMed1982

Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona).

Molecular, kinetic, and functional studies were carried out on erythrocytes and leukocytes in a Spanish male with G6PD deficiency, congenital nonspherocytic hemolytic anemia (CNSHA), and increased susceptibility to infections. G6PD activity was absent in patient's red cells and was about 2% of normal in leukocytes. Molecular studies using standard methods (WHO, 1967) showed G6PD in the patient to have a slightly fast electrophoretic mobility at pH 8.0 with otherwise normal properties (heat stability at 46 degrees C, apparent affinity for substrates, optimum pH, and utilization of substrate analogues). Other tests showed the patient's granulocytes to engulf latex particles normally, but to have impaired reduction of nitroblue tetrazolium and ferricytochrome-c as well as reduced iodination. Chemotaxis and random migration of the patient's granulocytes were normal as were myeloperoxidase, leukocyte alkaline phosphatase (LAP), and ultrastructural features. The molecular characteristics of G6PD in the patient differed from those of all previously reported variants associated with CNSHA, so the present variant was provisionally called G6PD Barcelona to distinguish it from other G6PD variants previously described. Possible mechanisms for the severe deficiency of G6PD in erythrocytes and granulocytes was investigated by studies on the immunologic specific activity of the mutant enzyme.

Adult↗
PubMed2026

Somatic likelihood tiering: an interpretable post-calling triage protocol for tumor-only whole-exome variant review.

Tumor-only whole-exome sequencing (WES) is used when matched normal tissue is unavailable, but one sample can produce thousands of variants. Somatic likelihood tiering (SLT) is an interpretable post-calling protocol that ranks Mutect2 calls into four review-priority tiers using population-frequency, germline-quality, cancer-knowledge, PureCN posterior, and clonal-hematopoiesis evidence. Layer 2 distinguishes common, rare-callable, and unevaluable gnomAD states; missing or unmatchable gnomAD evidence is not positive rarity evidence. On the SEQC2 HCC1395 benchmark, the callability-aware SLT-A row contained 101 calls, 78 truth variants, 77.2% PPV (95% Wilson confidence interval 68.1%-84.3%), and a Number Needed to Review (NNR) of 1.29 (1.19-1.47). The conservative SLT-C catchment retained 352 of 455 truth variants (77.4%, 73.3%-81.0%) and all tiers together retained 430 of 455 truth variants. SNV performance is the primary calibration frame: SLT-C retained 341 of 439 SNV truth variants, whereas indel results were exploratory because only 16 truth indels were available. Clinical cohorts are reported as recall and concordance versus partially dependent matched-normal Mutect2 references, not independent clinical sensitivity. Patient-level bootstrap intervals were principal: HdM-BLCA-1 SLT-A recall was 18.2% (14.0%-23.5%), and LUAD-TW SLT-A recall was 49.1% (26.6%-63.3%) among 32 evaluable patients. The HdM-BLCA-1 median SLT-A queue remained 1277 variants per patient, so SLT reduces first-pass candidate counts but does not measure review time or eliminate FFPE candidate-count burden. SLT provides an auditable tumor-only WES review queue, not a substitute for matched-normal sequencing, independent orthogonal validation, or definitive somatic classification.

Humans↗
PubMed1991

Inversion-duplication of bands q13----q21 of human chromosome 9.

Structural abnormalities involving heterochromatic regions of the human genome are difficult to characterize because these segments are G-band negative by GTG technique, a routinely used procedure in clinical cytogenetic laboratories. Chromosome abnormalities of such cases have gone undetected or were incorrectly characterized because these regions are so-called heteromorphisms or variants. Consequently, much anxiety has been aroused by the confusion between a chromosome abnormality and a normal heteromorphic variant. We report the first documented case with a so-called highly unusual h region of chromosome 9 which is not a variation but a structural rearrangement involving a paracentric inversion and a duplication. The major clinical features were psychomotor retardation, microcephaly, narrow palpebral fissures, renal and genital anomalies, vertebral anomalies, protruding tongue, and learning and behavioral problems. A concise review of variable duplicated segments of 9q is also provided.

Abnormalities, Multiple↗
PubMed2002

Cloning of two new splice variants of Siglec-10 and mapping of the interaction between Siglec-10 and SHP-1.

Using a three-hybrid strategy in yeast, we have cloned a new splice variant of Siglec-10, called Siglec-10 Sv3. This splice variant lacks part of exon 3, but keeps the reading frame, as well as the crucial regions for interaction with Sias and the motifs for intracellular signaling. The expression of Siglec-10 Sv3 in T- and B-cells was detected by RT-PCR. Moreover, cDNA of another new splicing form of Siglec-10, named Siglec-10 Sv4, was identified by RT-PCR. One common characteristic of all Siglec-10 splice forms (except for Siglec-10 Sv2) is their cytoplasmic tail with two ITIMs and one CD150-like sequence. We confirmed the recruitment of SHP-1 to the Siglec-10 cytoplasmic tail by Western blot analysis and demonstrated that this interaction depends on tyrosine phosphorylation. Mutational analyses showed that ITIM Y609 of Siglec-10 and the N-terminal SH2 domain of SHP-1 play a pivotal role in the interaction between Siglec-10 and SHP-1. Finally, we demonstrated that Siglec-10 was not able to bind SAP/SH2d1A, indicating that the so-called CD150-like motif in Siglec-10 might be a docking site for other signal transduction mediators.

Alternative Splicing↗
PubMed2000

Development of infant baboons' responses to graded bark variants.

We studied the development of infant baboons' (Papio cynocephalus ursinus) responses to conspecific 'barks' in a free-ranging population in the Okavango Delta, Botswana. These barks grade from tonal, harmonically rich calls into calls with a more noisy, harsh structure. Typically, tonal variants are given when the signaller is at risk of losing contact with the group or a particular individual ('contact barks'), whereas harsh variants are given in response to predators ('alarm barks'). We conducted focal observations and playback experiments in which we presented variants of barks recorded from resident adult females. By six months of age, infants reliably discriminated between typical alarm and contact barks and they responded more strongly to intermediate alarm calls than to typical contact barks. Infants of six months and older also recognized their mothers by voice. The ability to discriminate between different call variants developed with increasing age. At two and a half months of age, infants failed to respond at all, whereas at four months they responded irrespective of the call type that was presented. At six months, infants showed adult-like responses by responding strongly to alarm barks but ignoring contact barks. We concluded that infants gradually learn to attach the appropriate meaning to alarm and contact barks.

Animal Communication↗
PubMed2002

Possible co-regulation of genes associated with enhanced progression of mammary adenocarcinomas.

Tumor progression is a multistep process in which alterations in the expression of numerous gene products may give rise to highly malignant cellular variants. In the present study, we analyzed the differential expression of several genes in cellular variants of mammary adenocarcinomas with high or low malignancy potential, which originated in a common ancestor. To assess the generality of our findings, high and low malignancy variants were derived from two different mammary adenocarcinoma cell lines, namely DA3 and CSML cells. Of major importance is the fact that the differences between high- and low-malignancy variants observed in one system of mammary adenocarcinoma cells (DA3 cells) were identically reproduced in the other system of mammary adenocarcinoma cells (CSML cells). The high malignancy variants of tumors both DA3-high and CSML-high (previously called CSML-100), expressed higher levels of factors that induce monocyte migration than the low malignancy DA3-low and CSML-low (previously called CSML-0) variants. In addition, it was found that DA3-high and CSML-high cell variants expressed higher levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and matrix metalloproteinases (MMPs) than the low malignancy variants (DA3-low and CSML-low). These results suggest that MCP-1, IL-6 and MMPs potentially contribute to mammary adenocarcinoma progression and that their expression is regulated by a common pathway. The expression of MCP-1, IL-6 and MMPs in both DA3-high and CSML-high cells was up-regulated by tumor necrosis factor alpha (TNFalpha). The fact that TNFalpha exerted similar effects on the expression of these three factors in both cell systems raises the possibility of a coordinated co-regulation of tumor-promoting factors.

Adenocarcinoma↗
PubMed2002

FOR, a novel orphan nuclear receptor related to farnesoid X receptor.

We have identified and characterized a new amphibian orphan member of the nuclear receptor superfamily and termed it FOR1 (farnesoid X receptor (FXR)-like Orphan Receptor) because it shares the highest amino acid identity with the mammalian FXR. We also identified a variant of FOR1, called FOR2, which has 15 additional C-terminal amino acids. Both variants include an unusual insertion of 33 amino acids in the helix 7 region of the canonical ligand binding domain sequence, suggesting a unique structure for FOR. Northern blot analysis demonstrates that the FOR gene is highly expressed in adult and tadpole liver, kidney, and tail bud stage of the embryo. Detailed expression analysis using in situ hybridization indicates that FOR expression is first detectable at stage 30/31 in the presumptive liver region lasting until stage 41 with a peak level evident at stage 35/36. FOR forms heterodimeric complexes with retinoid X receptor (RXR) as demonstrated by biochemical and mammalian two-hybrid approaches. Gel mobility shift assays demonstrate that FORs form specific DNA-protein complexes on an FXR binding element consisting of an inverted repeat DNA element with 1 nucleotide spacing (IR1) from the phospholipid transfer protein gene promoter. Finally, although FORs do not exhibit constitutive transcriptional activity, frog gallbladder extract significantly augments the transcriptional activities of FORs.

Amino Acid Sequence↗
PubMed2025

OctopuSV and TentacleSV: a one-stop toolkit for multi-sample, cross-platform structural variant comparison and analysis.

MOTIVATION: Structural variants (SVs) influence gene regulation, disease progression, and diagnostics, yet integrating SV calls across platforms remains difficult due to inconsistent annotations, limited merging flexibility, and fragmented workflows. Ambiguous breakend (BND) annotations, which comprise many variant calls, are often discarded or misclassified, hindering variant characterization. Existing tools lack advanced merging operations essential for precise identification of disease-specific or somatic variants across samples or patient groups. Additionally, current SV analysis pipelines require extensive manual intervention and complex parameter tuning, compromising reproducibility and scalability. Addressing these gaps is crucial for improving the accuracy, interpretability, and clinical utility of SV analyses. RESULTS: We developed OctopuSV and TentacleSV to address these long-standing challenges in SV analysis. OctopuSV features a specialized BND correction module that converts ambiguous BND annotations into canonical SV types, recovering important variants that are often overlooked by existing tools. Additionally, it provides advanced set operations (difference, complement, custom-defined) that enable sophisticated variant filtering without programming expertise, critical for identifying tumor-specific SVs or variants unique to specific sample groups. TentacleSV completes our solution by automating the entire SV analysis process from raw sequencing data to high-confidence callsets, ensuring consistency and reproducibility across projects. Benchmarking across short-read and long-read platforms showed superior F1 score, complete SV type consistency compared to existing tools. Our framework enables experimental biologists and clinical researchers to perform sophisticated analyses ranging from cancer subtype-specific SV identification to multi-sample comparative studies without requiring specialized programming skills. AVAILABILITY AND IMPLEMENTATION: All codes are available at https://github.com/ylab-hi/OctopuSV; https://github.com/ylab-hi/TentacleSV.

Software↗
PubMed1989

Quantitative analysis of amyloid fibril protein in systemic organs of patients with familial amyloidotic polyneuropathy.

The purpose of this study was to develop a quantitative method for variant transthyretin (also called prealbumin) in amyloid-laden tissues of familial amyloidotic polyneuropathy (FAP). The variant transthyretin was extracted by using 70% formic acid solution in which the protein was solubilized completely and rapidly. The quantity of the variant transthyretin was measured by a radioimmunoassay (RIA). An immunoreactive species detected in the tissues of FAP was confirmed to be the variant transthyretin by reverse-phase high-performance liquid chromatography. The quantity of the variant transthyretin in the thyroid gland of 2 FAP patients was 9.90 and 9.76 micrograms/mg tissue, and that of the kidney was 4.03 and 6.27 micrograms/mg tissue, respectively, while its quantity in the liver was only 0.15 and 0.12 microgram/mg tissue. We present here a quantitative analysis of the distribution and predominance of amyloid deposits in systemic organs of FAP.

Adult↗
PubMed1996

The role of the estrogen receptor in tumor progression.

We will discuss two estrogen receptor (ER) variants that may play a role in breast cancer initiation or progression. One is a truncated receptor, which has been named the exon 5 ER deletion variant, and the other is called a hyper-sensitive variant of the ER that is sensitive to low levels of hormone. Both ER variants differ from the wild-type ER in their hormone binding domains (HBD). The exon 5 ER deletion variant lacks a large portion of the HBD, while the hyper-sensitive ER variant has a point mutation in a conserved region of the HBD. The exon 5 ER deletion variant is transcriptionally active in the absence of hormone, and is thus considered constitutively-active. In contrast, the hyper-sensitive ER variant is functionally active in response to subphysiological concentrations of estrogen. We speculate that both ER variants may form productive heterodimers with wild-type receptor to modify the normal function of ER in the breast.

Animals↗
PubMed1996

Alzheimer's disease and its Lewy body variant: a clinical analysis of postmortem verified cases.

OBJECTIVE: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. METHOD: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examination. RESULTS: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in the two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of homovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. CONCLUSIONS: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapy-ramidal side effects and have low levels of CSF HVA.

Aged↗
PubMed1995

Factors XWenatchee I and II: compound heterozygosity involving two variant proteins.

Variant factor X in an individual with a mild bleeding tendency was suspected based on deficient procoagulant activity (10-20% of normal) and antigen (30-35% of normal) levels of plasma factor X. Heteroduplex analysis of factor X gene exons indicated heterozygosity for mutations in both exons 6 and 4, confirmed by direct sequencing of the amplified exons. Substitution of C by T at nucleotide position 13,984 (Arg-139 to Cys) was found in the factor X gene exon 6 of the propositus. This mutation creates a BsmI site and the patient tested heterozygous for the BsmI cleavage involved, as did one of his two daughters. In addition, exon 4 was found to have the normal A and a novel C (Asn-57 to Thr) at nucleotide position 9338. The exon 4 mutation creates a BsaJI site, detectable after amplification mismatch to remove an existing BsaJI site. Both the patient and the second of his two daughters were heterozygous for this cleavage. The two variant proteins are called factors XWenatchee I (Arg-139 to Cys) and II (Asn-57 to Thr). A mixed variant isolate derived from the plasma of the propositus exhibited heavy/light chains of normal size, as well as an apparent single-chain molecule not dissociable by reducing agent. A single-chain molecule would be predicted for form I, if the mutation blocks processing cleavages that normally remove a tripeptide interposed between the heavy and light chains. A Western blot of partially purified factor X from the daughter who inherited the form I defect revealed a component migrating the same as the putative single-chain species. Based upon the factor X activity vs. antigen ratios for the propositus and both daughters, both forms I and II are probably dysfunctional molecules.

Amino Acid Sequence↗
PubMed1987

Biochemical characterization of familial amyloidotic polyneuropathy in various districts of Japan.

The purpose of this study is to disclose the molecular basis of type I familial amyloidotic polyneuropathy (FAP) in Japan. Amyloid fibril protein of type I FAP consists of a variant transthyretin (also called prealbumin) with one amino acid substitution of methionine-for-valine at position 30. This variant transthyretin is present in the serum as a precursor protein of amyloid. A radioimmunoassay (RIA) has been established to detect the variant transthyretin. All the 94 patients with FAP who originate from various districts in Japan have the variant transthyretin, but any one of 78 healthy adults of families with FAP do not have it. Half of the symptom-free children of FAP patients have the variant transthyretin even before clinical manifestations appear. The RIA is widely applicable for early diagnosis. The methionine-for-valine substitution is due to a base change from guanine to adenine at the first letter of the valine codon at position 30. Type I FAP in Japan is considered to be a molecular disorder of transthyretin. Since the age of onset ranges from twenties to forties, genetic counseling is recommended to prevent the transmission of this intractable disorder to the next generation.

Adolescent↗
PubMed2005

Cloning, expression, and functional characterization of human cyclooxygenase-1 splicing variants: evidence for intron 1 retention.

Recently, a splicing variant of cyclooxygenase (COX)-1, arising via the retention of its intron 1, was identified in canine. It was called COX-3 and was reported to be differentially sensitive to inhibition by various nonsteroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen (Chandrasekharan et al., 2002). However, the existence of an orthologous splicing variant in human tissues has been questioned due to a reading frame shift and premature termination. In this study, we first confirmed the existence of intron 1-retained COX-1 in certain human tissues at both the mRNA and protein levels. Molecular biology studies revealed that three distinct COX-1 splicing variants exist in human tissues. The most prevalent of these variants, called COX-1b1, arises via retention of the entire 94 base pair (bp) of intron 1, leading to a shift in the reading frame and termination at bp 249. However, the other two variant types, called COX-1b2 and COX-1b3, retain entire intron 1, but they are missing a nucleotide in one of two different positions, thereby encoding predicted full-length and likely COX-active proteins. Functional studies revealed that the COX-1b2 is able to catalyze the synthesis of prostaglandin F2alpha from arachidonic acid with Km and Vmax values of 0.54 microM and 3.07 pmol/mg/min, respectively. However, no significant differential selectivity for inhibition by selected NSAIDs was observed. Accordingly, we conclude that intron 1-retained human COX-1 is not likely to be the therapeutic target of acetaminophen or a candidate of COX-3.

Acetaminophen↗
PubMed1988

Isolation and expression of cDNA clones coding for two sequence variants of Xenopus laevis histone H5.

We have cloned and characterized cDNAs coding for two variants of Xenopus laevis H5 histone protein (previously called H1s). cDNA was synthesized from RNA of immature erythrocytes in a single reaction using a modification of the method of Gubler and Hoffman [Gene 25 (1983) 263-269], and blunt-end ligated into the HincII site of the phage vector M13mp9. Immunological screening with a polyclonal antibody yielded two clones expressing H5 peptide. Sequence characterization revealed that both clones contained partial cDNA inserts and that the smaller 340-bp clone initiated reverse transcription within the coding region, at a site rich in adenine. Rescreening of the cDNA bank by nucleic acid hybridization produced eleven additional H5 clones, one of which coded for a second variant of H5. These two variants, called XLH5A and XLH5B, are very similar in sequence and code for proteins of 195 and 193 amino acids, respectively, which may be the H1D and H1E variants observed previously. XLH5, avian H5 and human H1O share identity at both nucleotide and amino-acid sequence levels. Further, the XLH5-coding mRNA is likely polyadenylated and lacks the highly conserved, 23-nucleotide dyad symmetry element found within the 3' untranslated regions of most histone-coding mRNAs.

Amino Acid Sequence↗