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PubMed2026

Disruption of Polycystin Ciliary Localization and Channel Function by Autosomal Dominant Polycystic Kidney Disease-Causing Polycystin-1 Variants.

KEY POINTS: We developed assays to measure genetic variant effects on polycystin-1, the protein mutated in most autosomal dominant polycystic kidney disease. All tested pathogenic variants disrupted either polycystin-1 ciliary trafficking or channel function. Trafficking and channel function of some pathogenic variants was restored by low temperature culture to promote polycystin folding. BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading monogenic cause of kidney failure and affects millions of people worldwide. Despite the prevalence of ADPKD, limited mechanistic understanding has hindered therapeutic development. Most ADPKD is caused by loss-of-function variants in polycystin-1 (PC1). METHODS: We developed assays that quantify the effect of nontruncating variants on PC1 ciliary localization, membrane trafficking, and polycystin channel function. RESULTS: We evaluated 29 nontruncating variants in PC1 and found that pathogenic variants disrupt two molecular phenotypes: ( 1 ) localization of PC1 at the primary cilium or ( 2 ) polycystin ion channel activity. Ciliary localization of a subset of polycystin variants was restored when cells were cultured at low temperature. A subset of variants with localization restored by low temperature formed functional channels. CONCLUSIONS: This study demonstrated that disruptions in polycystin ciliary trafficking and channel function are common causes of ADPKD. Defects in ciliary trafficking and channel function can be rescued for a subset of pathogenic variants, establishing a foundation for polycystin-targeted therapies in ADPKD.

Polycystic Kidney, Autosomal Dominant↗

PubMed2006

Effects of acid water exposure on plasma cortisol, ion balance, and immune functions in the "cobalt" variant of rainbow trout.

This study was undertaken to examine physiological responses to acidification of environmental water in the "cobalt" variant of rainbow trout (Oncorhynchus mykiss), which exhibits malformation of the pituitary, by following changes in plasma levels of cortisol and electrolytes, blood pH, gill Na(+), K(+)-ATPase activity, and immune functions after exposure to acid water (pH 4.5). Resting levels of plasma cortisol and lysozyme were significantly lower in the cobalt variant than in the normal trout, whereas plasma ceruloplasmin was significantly higher in the cobalt variant, suggesting that some endocrine factors, lacking or deficient in the cobalt variant, are important for the regulation of its immune functions. Blood pH was slightly but significantly lower in the cobalt variant at rest. After exposure to acid water for 24 h, both the normal trout and cobalt variant showed a significant elevation in plasma cortisol, although the increased level in the cobalt variant was still lower than that in the normal trout transferred to neutral water. No differences were seen in blood pH, plasma electrolytes, and gill Na(+), K(+)-ATPase activity between the normal trout and the cobalt variant, indicating that the cobalt variant regulates ion balance when exposed to acid water, despite malformation of the pituitary. Although the normal trout showed a reduction in plasma lysozyme level after acid exposure, there was no significant change in the cobalt trout. Adverse effects of pituitary malformation on ion balance and immune functions may be compensated by extrapituitary factors in the cobalt variant when it is exposed to acid water.

Animals↗

PubMed1998

Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene.

The high-affinity sulfonylurea receptor (SUR1) is, as a subunit of the ATP-sensitive potassium channel, an important regulator of insulin secretion in the pancreatic beta-cell. The aim of this study was to examine if genetic variability of the SUR1 gene was associated with NIDDM or altered pancreatic beta-cell function. Mutational analysis of all the 39 SUR1 exons, including intron-exon boundaries, in 63 NIDDM patients revealed two missense variants, five silent variants in the coding region, and four intron variants. The two missense variants (Asp673Asn and Ser1369Ala) and two sequence variants (ACC-->ACT, Thr759Thr and a c-->t intron variant in position -3 of the exon 16 splice acceptor site) were examined for association with NIDDM and for a possible influence on insulin and C-peptide secretion after intravenous glucose and tolbutamide loads in a random sample of unrelated, healthy, young Danish Caucasians. The Asp673Asn variant in exon 14 was only identified in one NIDDM patient, and the allelic frequency of the Ser1369Ala was similar among 247 control subjects (0.38 [95% CI 0.34-0.42]) and 406 NIDDM patients (0.40 [0.37-0.43]). The allelic frequency of the silent exon 18 Thr775Thr variant was 0.051 (0.035-0.067) in NIDDM patients (n=392) and 0.027 (0.013-0.041) in control subjects (n=246; chi2=4.99, P=0.03). The allelic frequency of the intron variant was similar among NIDDM patients (0.45 [0.42-0.48]) and control subjects (0.44 [0.40-0.48]). Of 386 NIDDM patients, 17 had the combined genotype exon 18 C/T and intron -3c/-3t (0.044 [0.024-0.064]), whereas 3 of 243 control subjects had the same combined genotype (0.012 [0-0.026]; chi2=4.87, P=0.03; odds ratio: 3.69 [1.07-12.71]). Of 380 unrelated, healthy, young Danish Caucasians, 10 (0.026 [0.010-0.042]) had the combined at-risk genotype. These subjects had, on average, a 50% reduction in serum C-peptide and a 40% reduction in serum insulin responses upon tolbutamide injection (P=0.002 and P=0.05, respectively) but normal serum C-peptide and insulin responses upon glucose injection. In conclusion, a silent polymorphism in exon 18 of the SUR1 gene is associated with NIDDM in a Danish Caucasian population. In combination with an intron variant, the association is higher, and young, healthy carriers of the intragenic combination have reduced serum C-peptide and insulin responses to a tolbutamide load.

ATP-Binding Cassette Transporters↗

PubMed2026

[Genetic analysis of a male with Multiple morphological abnormalities of sperm flagella combined with sperm head abnormalities due to compound heterozygous variants of DNAH1 gene and a literature review].

OBJECTIVE: To explore the clinical phenotype and genetic etiology of a male with Multiple morphological abnormalities of sperm flagella (MMAF) combined with sperm head abnormalities due to compound heterozygous variants of DNAH1 gene, with an aim to provide guidance for assisted reproductive technology in his family. METHODS: A man with MMAF combined with sperm head abnormalities who visited Women and Children's Hospital of Ningbo University in October 2024 was selected as study subject. Clinical data of the patient's family were retrospectively collected. Peripheral blood samples were collected from the patient and his spouse, and G-banding karyotyping and whole exome sequencing (WES) were carried out. Candidate variants were validated by Sanger sequencing. Conservation of the DNAH1 protein was queried on the UCSC website. The difference between wild type and variant DNAH1 proteins were analyzed using AlphaFold v3.0.1 and PyMOL v2.5.6. The pathogenicity of variant was rated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). Previous literature was searched using keywords "DNAH1 gene" and "multiple morphological abnormalities of the sperm flagella" on CNKI, Wanfang Data Knowledge Service Platform, and PubMed database to identify cases of MMAF attributed to biallelic DNAH1 gene variants. The retrieval period was set from the establishment of the databases to December 31, 2025. The genotypes and clinical phenotypes of patients with biallelic DNAH1 mutations were analyzed. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2023-094). RESULTS: The 30-year-old patient and his 30-year-old wife had infertility for 2 years. Semen analysis revealed no motile sperm and a 99.0% abnormal morphology rate. Typical MMAF was observed with phase-contrast microscopy. Sperm morphology analysis revealed abnormalities of the head, neck, and tail with an approximate ratio of 9:5:1. The patient's karyotype was 46,XY, and his wife's karyotype was 45,X[4]/47,XXX[1]/46,XX[84]. WES and Sanger sequencing revealed that the patient harbored compound heterozygous variants of the DNAH1 gene, namely c.1435_1444+3del and c.12204_12206del (p.Asn4069del), but their origin remained unidentified. UCSC genome browser query results showed that the amino acid residue at position 4 069 of the DNAH1 protein is highly conserved across various species. Protein structure prediction reveals that, in the wild-type DNAH1 protein, the Asparagine at position 4 069 (Asn4069) can form hydrogen bonds with the Leucine on the main chain at position 4 086 (Leu4086) and the Serine on the side chain at position 4 087 (Ser4087). The c.12204_12206del variant, resulting in deletion of Asn4069, disrupts these hydrogen bonds and does not generate any compensatory interactions. Based on the ACMG guidelines, the c.1435_1444+3del variant was predicted to be likely pathogenic (PM2_Supporting+PVS1), and the c.12204_12206del(p.Asn4069del) variant was rated as likely pathogenic (PM2_Supporting+PM4+PM3+PP4). The couple had elected for in vitro fertilization using donor sperm. During this cycle, 12 oocytes were retrieved, 10 oocytes were successfully fertilized, 1 embryo and 6 blastocysts were obtained. Following the first transfer of a frozen-thawed blastocyst, implantation of an empty gestational sac occurred, which led to a miscarriage. After the second transfer of a high-quality blastocyst, the embryo split into twins following implantation, and the spouse had selected fetal reduction. The gestational age was 33+3 weeks on June 1, 2026. Literature review identified three studies reporting biallelic mutations of the DNAH1 gene in association with MMAF combined with sperm head abnormalities. Together with the patient from this study, a total of 20 patients were included in the analysis. The rate of sperm flagellar abnormalities in these patients was above 80.0%, while the rate of sperm head abnormalities has ranged from 12.0% to 100.0%. In four patients, the genetic basis was unknown. In the remaining 16 patients, 35 mutations were detected, with c.8626-1G>A being the most common (22.9%, 8/35). CONCLUSION: This patient showed MMAF with frequent sperm head defects. Compound heterozygous variants of the DNAH1 gene probably underlay these abnormalities, which in turn has led to his primary infertility. This study revealed the phenotypic variability of MMAF and broadened the mutational spectrum of the DNAH1 gene.

Humans↗

PubMed2026

'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).

BACKGROUND: Large-scale functional assays, including multiplex assays of variant effect, have substantial potential to resolve variants of uncertain significance (VUS), particularly for rare missense variants where clinical and population evidence are limited. The ClinGen assay-level clinical validation framework described by Brnich et al provided baseline guidance for the use of functional data for variant classification. However, clear consensus regarding construction of variant 'truthsets' by which to clinically validate functional data remains lacking. METHODS: CanVIG-UK developed consensus recommendations for truthset construction through an iterative national consultation process involving the CanVIG Steering Advisory Group (CStAG), wider CanVIG-UK membership, and engagement with international functional genomics experts. Consultation was based on previous analyses of 2,120 truthset constructions examining the impact of truthset composition on evidence point allocation within the ClinGen assay-level clinical validation framework. RESULTS: Across several consultations, CanVIG-UK established nine guiding principles and seven best-practice recommendations for assay-level clinical validation, using the assumed context of an assay for a cancer susceptibility gene where loss-of-function is the mechanism of pathogenicity. The principal recommendation stipulates, where assays are intended for use in interpretation of largely missense variants, the truthset used to validate should comprise only missense variants. Rather than mixtures of different variant types which may serve to over-estimate assay performance. Additional recommendations support option for relaxation of truthset stringency to improve power, augmentation of benign missense truthsets with systematically derived 'proxy-clinical' benign variants, independent clinical validation separate from assayist-defined validation, and careful evaluation of missense score distributions against that of protein-truncating and synonymous variants. Guidance is also provided for scenarios with limited pathogenic truthset availability and for assays reporting multiple deleterious zones or readouts. CONCLUSIONS: The CanVIG-UK principles and recommendations for truthset construction upon the ClinGen assay-level clinical validation framework, while aiming to form a baseline for future discussion regarding other functional and disease contexts and helping to address the gap between publication of new data and routine clinical implementation.

Journal Article↗

PubMed2001

A molecular variant of the APC gene at codon 1822: its association with diet, lifestyle, and risk of colon cancer.

The adenomatous polyposis coli (APC) gene is important in the etiology of colon cancer. Although germ-line mutations of this gene rarely occur in the population, less penetrant variants of the gene have been reported. One variant, producing an aspartate to valine change at codon 1822 (D1822V) [corrected] has been previously reported as having an allele frequency of 10%. The purpose of this study was to determine whether this D1822V [corrected] variant of the APC gene is associated with colon cancer and whether its association is influenced by other genetic or environmental factors. We used data collected as part of a multicenter study of 1,585 incident cases of colon cancer and 1,945 age- and sex-matched population-based controls to evaluate genetic, dietary, and environmental associations with the D1822V [corrected] variant of the APC gene. The frequency of the valine/valine allele at codon 1,822 was 22.8% in this population. In the control population, 61.5% were homozygote wild type, 33.3% were heterozygotes, and 5.2% were homozygote variant. Cases were slightly less likely to have the homozygous variant APC genotype than were controls [odds ratio (OR), 0.8; 95% confidence interval (CI), 0.6-1.1]; for those diagnosed after age 65, the homozygous APC variant was associated with reduced risk of colon cancer (OR, 0.6; 95% CI, 0.4-1.0). Assessment of the homozygous APC variant with dietary, genetic, and environmental factors showed that individuals with this genotype were at lower risk if they consumed a low-fat diet (OR, 0.2; 95% CI, 0.1-0.5) relative to those who were homozygous wild type and ate a high-fat diet. This finding was specific to a low-fat diet and was unrelated to other dietary variables. These results suggest that the codon 1,822 variant of the APC gene may have functional significance. Individuals who have the valine/valine variant of this gene may be at reduced risk of colon cancer if they eat a low-fat diet.

Aged↗

PubMed1992

Molecular abnormalities of a human glucose-6-phosphate dehydrogenase variant associated with undetectable enzyme activity and immunologically cross-reacting material.

Among a large number of glucose-6-phosphate dehydrogenase (G6PD) variants associated with different severity of clinical manifestations, enzyme deficiency, and kinetic abnormalities found in humans, only one variant exhibits no measurable activity and lacks an immunologically cross-reacting material in blood cells and other tissues. The mRNA content of the patient's lymphoblastoid cells was found to be normal, and the size of mRNA was also normal (i.e., approximately 2.4 kb). Western blot hybridization indicated that the patient's cells did not produce cross-reacting material. The variant mRNA was reverse transcribed and amplified by PCR. Nucleotide sequencing of the variant cDNA showed the existence of three nucleotide base changes, i.e., a C----G at nucleotide 317 (counting from adenine of the initiation codon), which should cause Ser----Cys substitution at the 106th position (counting from the initiation Met); a C----T at nucleotide 544, which induces the Arg----Trp at the 182d position; and a C----T at nucleotide 592, which induces Arg----Cys at the 198th position of the protein. The existence of three mutation sites was confirmed by sequencing of selected regions of the variant gene. No base deletion or frameshift mutation was found in the variant cDNA. No nucleotide change was detected in the extended 5' region, which included the most distal cap site. When the variant cDNA was expressed in Escherichia coli, the G6PD activity was approximately 2% of that expressed by the normal cDNA, and cross-reacting material was undetectable. However, when the variant mRNA was expressed in the in vitro translation system of rabbit reticulocytes, the variant protein was produced. These results suggest that extremely rapid in vivo degradation or precipitation of the variant enzyme induced by the three amino acid substitutions could be the major cause of the molecular deficiency.

Base Sequence↗

PubMedDate not supplied

Evaluation of MUC1 splice variants as prognostic markers in patients with ductal carcinoma in situ of the breast.

Despite intense research in the field of breast cancer it still remains the most common cancer in women in the Western world. A decreasing trend in mortality was mainly achieved by improved early detection which led to an increased incidence of ductal carcinoma in situ (DCIS) of the breast. For the patient's prognosis and the administration of a patient-tailored therapy strategy it is crucial to identify diagnostic and prognostic markers for high-risk DCIS patients. MUC1 is associated with tumour aggressiveness in human breast cancer. Recent studies used MUC1 splice variant A to identify malignant thyroid cancer. In the present study we have examined the usefulness of MUC1 splice variants as prognostic markers in DCIS. We used laser capture microdissection of paraffin-embedded tissue to isolate RNA from isolated tumour cells and determined the MUC1 splice variant distribution by RT-PCR. In the majority of cases variant B was more highly expressed than variant A. This was true for pure DCIS (66%) as well as for DCIS with adjacent invasive cancer (66%). In 7 out of 18 cases (38%) of pure DCIS variant A was not expressed at all. In DCIS with adjacent invasive cancer only 2 samples out of 12 showed this expression pattern (16%). The situation that variant A was more highly expressed than B, or that variant B was not expressed at all, was similar for pure DCIS (27%) and for DCIS with adjacent invasive cancer (33%). The present study describes the differences of MUC1 splice variant expression in pure DCIS compared to DCIS with adjacent invasive cancer. A discriminating pattern of MUC1 splice variants could not be demonstrated.

Alternative Splicing↗

PubMed2004

[Identification and characterization of alternativly splicing variants for murine mater gene].

Mater encoding an oocyte-specific autoantigen,and is associated with premature autoimmune ovarian dysgenesis (AOD) in mouse. Based on RT-PCR, cDNA cloning, screening, sequencing and analysis, we have detected a total of four Mater splice variants, designated as variant B, E, F and G. All these splicing forms are in frame in terms of expected protein products. Among these, B was consistent with the previous report, whereas E, F, G belong to novel splice variants that have not been reported previously. Variant E lacks exon 6, variant F both lacks exon 10 and retains a part of intron 8, variant G lacks part of exon 14, and variant H lacks part of exon 13. The cDNA sequences at all the exon-intron boundaries confirms to the "GT-AG" splicing rule. Variant B, E, F exist in all the four strains. Variant G exists only in SWR/J. According to the cDNA sequences of these four splice variants, amimo acid sequences of the corresponding expected protein isoforms were deduced, and their potential functional effects were predicted in this thesis. Further identification and characterization of these expected protein isoforms would provide valuable information for their functional importance.

Alternative Splicing↗

PubMed1979

[Frequency of chromosome variants in human populations].

Chromosome variants were analyzed in the course of the population chromosome investigation of 6000 newborns and clinical cytogenetic studies of 403 married couples with recurrent spontaneous abortions, stillbirths or offsprings having congenital malformations or Down's syndrome. The following variants were determined: 1) Igh+, 9gh+, 16gh+ - the enlargement of the secondary constrictions of the size, more than 1/4 of the long arm of the chromosome; 2) Dp+ or Gp+ - the enlargement of the short arms of acrocentrics, their size being more than the short arm of the chromosome 18; 3) Ds+ or Gs - large satellites of the acrocentrics which are equal or more than the thickness of the chromatids of the long arms; 4) Es+ - satellites on the short arms of the chromosomes 17 or 18; 5) Dss of Gss - double satellites; 6) Yq+ - the enlargement of the long arm of Y chromosome, the size of which being more than G chromosome; 7) Yq- - deletion of the long arm of Y chromosome, the size of the long arm being less than chromosomes 21--22. The total frequency of variants in newborns was 12.8/1000 births. The incidence of different types of variants per 1000 births was as follows: Igh+ - 0.33; 9gh+ - 0.17; 16gh+ - 0.50; Ds+ - 2.33; Dp+ - 1.50; Dp- - 0.17; Gs+ - 0.83; Gp+ - 2.17; Yq+ - 6.91/1000 males; Yg- - 0.99/1000 males; double variants - 0.33; other variants - 0.33. 4.0% of married couples with recurrent spontaneous abortions had major chromosome aberrations, 14.6% - extreme variants of chromosomes. Among 113 couples with the history of congenital malformations in their offsprings major chromosome abnormalities were found in 4.4%, chromosome variants - 13.3%. The frequency of chromosome variants among 139 patients with Down's syndrome was 7.2%. In one case Robertsonian translocation t(DqGa) was determined. The most frequent types of variant chromosomes were Ds+, Dp+, Es+, Yq+.

Abortion, Habitual↗

PubMed1989

Atherosclerosis- and age-related multinucleated variant endothelial cells in primary culture from human aorta.

Endothelial cells were cultured from human aortas and inferior venae cavae of autopsied subjects ranging in age from infancy to 85 years. Endothelial cells in 32 of more than 100 attempted cultures were pure enough for evaluation. Emerged endothelial cells in primary culture were classified into two types: typical endothelium and variant endothelium. Typical endothelial cells were small, round to polygonal shaped, and were arranged uniformly. Their diameter ranged from 50 to 70 microns. Variant endothelial cells were larger, ranging from 100 to 200 microns in diameter, and giant endothelial cells measuring more than 250 microns in diameter were scattered among them. Variant endothelial cells were usually multinucleated and possessed endothelium-specific markers of vWF and Weibel-Palade bodies. No incorporation of [3H]thymidine was found in the nuclei of cultured variant endothelial cells. Although most cultured endothelial cells were of the typical type, variant endothelial cells were interspersed throughout the culture. The ratio of variant endothelial cells to typical cells correlated well with the severity of atherosclerosis, but less so with aging. The number of variant endothelial cells in cultures from inferior venae cavae was slight and constant throughout all age groups. The presence of multinucleated endothelial cells in in vivo aortas was confirmed by both scanning and transmission electron microscopy. They sometimes existed in colonies in the aortas from elderly subjects with intimal-thickened or advanced atherosclerotic lesions. These results indicate that variant endothelial cells were present in vivo and their ratio in primary culture reflected the in vivo population. It is likely that these cells were formed by adhesion of adjacent typical endothelial cells and that this process was affected more by atherosclerosis than by aging. Although it is not clear if the multinucleated variant cells were formed before the formation of atherosclerotic plaque or after the plaque formation, they will contribute to further development of atherosclerotic lesions, which in turn cause malfunction of the cell membrane. We suggest that there is a cyclic effect of these processes for multiplication of the variant endothelial cells and advancement of atherosclerotic lesions.

Adolescent↗

PubMed1989

Detection of 10 variants of biliverdin reductase in rat liver by two-dimensional gel electrophoresis.

We have identified and characterized multiple forms of biliverdin reductase (BVR) in control rat liver cytosol. Two-dimensional electrophoresis of the purified BVR resolved a minimum of 10 discrete protein zones. All 10 proteins were BVR as judged by immunological cross-reactivity toward rabbit anti-rat BVR. Based on the isoelectric focusing pattern of separation, the BVR variants could be organized into five net-charge groups designated as BVR-IEF1 to BVR-IEF5 and three molecular mass groups designated as BVR-MW1-BVR-MW3, respectively. The pI values of the net-charge groups were: BVR-IEF1, 6.23; IEF2, 5.91; IEF3, 5.76; IEF4, 5.61; IEF5, 5.48. The Mr values of the molecular mass groups were: BVR-MW1, 30,400; MW2, 30,700; MW3, 31,400. Single dimension slab gel isoelectric focusing offered greater resolution of the net charge variants, and BVR-IEF3 was further resolved into two variants, IEF3a and IEF3b, with pIs of 5.77 and 5.75, respectively. The six net-charge variants also resolved on a preparative chromatofocusing column and were designated as BVR-CF1-BVR-CF6. The pH values of the peak fractions were: BVR-CF1, 6.91; CF2, 6.33; CF3, 6.03; CF4, 5.82; CF5, 5.45; CF6, 5.27. Correspondence between the isoelectric focusing net-charge variants and the chromatofocusing net-charge variants was established. The Mr and net-charge variants did not represent partially degraded forms of biliverdin reductase produced during purification since the pattern of resolution of variants on slab gel isoelectric focusing or two-dimensional electrophoresis did not change by purifying the proteins in the presence of protease inhibitors and 5 mM EDTA. BVR-CF2 and BVR-CF4 were purified and examined for pH-dependent cofactor requirements for activity. Both net-charge variants and two pH optima that were cofactor-dependent; maximum activity with NADPH, however, was at pH 8.5 and with NADH at pH 6.7. With both variants, however, a higher catalytic rate was observed with NADH than with NADPH at their respective pH optima. Furthermore, BVR-CF2 exhibited a higher catalytic rate than did BVR-CF4 with either cofactor throughout the pH range of 5-9.

Animals↗

PubMed1981

[Membrane proteins of active and inactive variants of Actinomyces sp. 26-115, a producer of actinomycin C].

Some properties of the membrane proteins of Actinomyces sp. 26-115, i. e. its active variant and a variant not producing actinomycin C were studied comparatively. The membrane proteins of both variants of all ages tested represented a heterogenous fraction including about 30 protein components with a molecular mass of 17000 to 500000. There were differences in the protein component composition of the active and inactive variants. The membrane proteins of the active variant contained much more disulfide bonds than those of the inactive variant. It was shown in the model experiments on the protein binding of the phospholipid-lecithin membranes that the membrane proteins of the active variant bound higher amounts of lecithin during the whole developmental cycle than those of the inactive variant. It is suggested that the membrane proteins of the active variant had conformation differences as compared to those of the inactive variant.

Actinomyces↗

PubMed1983

Recombination in simian virus 40-infected cells. Structure of naturally arising variants ev-2114, ev-2102, and ev-1110.

The complete nucleotide sequence has been determined for three newly cloned evolutionary variants from two different independently generated evolutionary series (1100 and 2100 series) of simian virus 40 (SV40). These naturally arising variants, designated ev-1110, ev-2102, and ev-2114, were isolated after five high multiplicity serial passages. The structure of the variants consists of a monomeric unit tandemly repeated four times (ev-2102 and ev-2114) or six times (ev-1110) in the variant genome; the variants have four or six copies, respectively, of the viral origin signal for DNA replication. The DNA content in the three variants is vastly different in that the genome of variant ev-2114 contains only rearranged viral sequences, while variant ev-2102 contains a substitution with monkey DNA sequences consisting of a nearly complete dimeric unit of Alu family sequences as well as less repetitive sequences and variant ev-1110 contains monkey DNA sequences derived solely from repetitive alpha-component DNA. Recombination events, cellular sequences, and structural features of these and other naturally arising SV40 variants are compared.

Base Sequence↗

PubMed1995

Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells.

Mammary cancers often develop into a hormone-independent and antagonist-resistant growth phase. The molecular mechanisms of this transition are not clear. Recently, it has been proposed that estrogen receptor variants derived from alternative splicing might lead to dominant positive transcription factors acting on estrogen response elements, even in the absence of the hormone. We show here the comprehensive analysis of expression of estrogen receptor variants lacking internal exons in the estrogen receptor-positive mammary carcinoma cell line MCF-7, in a tumor sample, and in healthy breast tissue taken from reduction surgery. Variants are identified by reverse transcription PCR and hybridization to exon-specific oligonucleotide probes. In MCF-7 cells we detected 10 variants including 5 that have not been described before. Skipping one, two, or three exons occurs. The major variants detected in the cell line are also present in normal and neoplastic tissues. Quantitative variations allow no conclusions of a potential involvement of the variants in neoplastic processes. Rather, the variants appear to be present normally and thus might have a physiological role. Given the expression of the variants in normal tissue, and given the expression of potentially dominant positive variants in conjunction with potentially dominant negative ones, we suggest that these variants do not account for hormone antagonist resistance.

Amino Acid Sequence↗

PubMed1998

The morphological variants of papillary carcinoma of the thyroid: a clinico-pathological study--AFIP experience. Armed Forces Institute of Pathology.

Many variants of papillary carcinoma of thyroid have been described. Identification of some of these may have prognostic implications. Eighty-two cases of papillary carcinoma of the thyroid diagnosed at Armed Forces Institute of Pathology, Rawalpindi over a six year period were reviewed with the aim of identifying these variants. Fifty-eight (70.7%) were classical papillary carcinoma. Thirteen (15.9%) had follicular variant, 6 (7.3%) columnar cell variant and 3 (3.7%) had tall cell variant. The mean age at diagnosis was 27 years for classical papillary carcinoma, 46 years for follicular variant, 61 years for columnar cell variant and 52 years for tall cell variant. The columnar cell variant had a more aggressive clinical presentation than others. Tall cell, columnar cell and diffuse sclerosing variant have a poor prognosis. An effort should be made to identify them on histopathology so that specific therapy can be planned.

Adult↗

PubMed2026

The Animal Variant Classification Guidelines v2: An Update With New Criteria and Improved Clarifications.

The Animal Variant Classification Guidelines (AVCG) were developed to standardize and objectify the classification of putative disease-causing variants. These guidelines are sufficiently reproducible and are used to classify previously published and new disease-causing variants across species. Here, the guidelines are updated (AVCG.v2), based on a three-phase decision process. Overall, four new criteria and seven clarifying comments were added. The number of criteria has increased from 23 to 27, with three new criteria supporting pathogenicity and one new criterion supporting benign classification. Pharmacogenomic variants were determined to fall within the scope of the guidelines. These updated guidelines are being used by the Variant Pathogenicity Working Group (VPWG), part of the Animal Genetic Testing Standardization standing committee, which is a committee of elected members of the International Society for Animal Genetics (ISAG). Under the auspices of ISAG, the VPWG retrospectively classifies published putative disease-causing variants. The pathogenicity label for a variant will be presented in the variant tables of Online Mendelian Inheritance in Animals (OMIA; https://omia.org/). The AVCGv.2 criteria and recommendations were developed by the expertise of the animal genetics community and the ISAG Executive Committee through the Animal Genetics Testing Standardization Committee endorses and strongly encourages their use to evaluate the evidence supporting pathogenicity of putative disease-causing variants.

Animals↗

PubMed2025

Germline variants in CDKN2A wild-type melanoma prone families.

Germline pathogenic variants in CDKN2A are well established as an underlying cause of familial malignant melanoma. While pathogenic variants in other genes have also been linked to melanoma, most familial cases remain unexplained. We assessed pathogenic germline variants in 360 cancer-related genes in 56 Norwegian melanoma-prone families. The index cases were selected based on familial history of melanoma and/or multiple primary melanomas, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants in BRCA2, MRE11, ATM, MSH2, CHEK2, and AR. One family member with melanoma (not index case) carried a pathogenic variant in MAP3K6. In addition, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance in xeroderma pigmentosum-related genes. In particular, XPCL48F was found in 8 indexes; thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (0.02-0.03; P-values from 0.007 to 0.014). In conclusion, we found that several melanoma-prone families have pathogenic variants in genes not usually linked to melanoma.

Humans↗