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PubMed1993

A novel silent variant at codon 711 and a variant at codon 708 of the APP sequence detected in Spanish Alzheimer and control cases.

Pathogenic mutations have been identified in exons 16 and 17 of the beta-amyloid precursor protein (APP) gene in some cases of early onset Alzheimer's disease. Screening of these exons in a number of familial and sporadic cases of Alzheimer's disease in Spain, resulted in the identification of a novel silent variant at codon 711 whose relevance to the AD pathogenesis remains unclear. The 708 variant was also detected in one of normal controls.

Alzheimer Disease↗

PubMed2003

Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complementation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes.

The oxidized guanine lesion 7,8-dihydro-8-oxo-2'-deoxyguanosine (OG) is highly mutagenic, resulting in G:C to T:A transversion mutations in the absence of repair. The Escherichia coli adenine glycosylase MutY and its human homolog (hMYH) play an important role in the prevention of mutations associated with OG by removing misincorporated adenine residues from OG:A mismatches. Previously, biallelic mutations of hMYH have been identified in a British family (Family N) with symptoms characteristic of familial adenomatous polyposis (FAP), which is typically associated with mutations in the adenomatous polyposis coli (APC) gene. Afflicted members of this family were compound heterozygotes for two mutations in hMYH, Y165C and G382D. These positions are highly conserved in MutY across phylogeny. The current work reveals a reduced ability of the hMYH variants compared to wild-type (WT) hMYH to complement the activity of E.coli MutY in mutY((-)) E.coli. In vitro analysis of the corresponding mutations in E.coli MutY revealed a reduction in the adenine glycosylase activity of the enzymes. In addition, evaluation of substrate affinity using a substrate analog, 2'-deoxy-2'-fluoroadenosine (FA) revealed that both mutations severely diminish the ability to recognize FA, and discriminate between OG and G. Importantly, adenine removal with both the mutant and WT E.coli enzymes was observed to be less efficient from a mismatch in the sequence context observed to be predominantly mutated in tumors of Family N. Interestingly, the magnitude of the reduced activity of the E.coli mutant enzymes relative to the WT enzyme was magnified in the "hotspot" sequence context. If the corresponding mutations in hMYH cause similar sensitivity to sequence context, this effect may contribute to the specific targeting of the APC gene. The lack of complementation of the hMYH variants for MutY, and the reduced activity of the Y82C and G253D E.coli enzymes, provide additional circumstantial evidence that the somatic mutations in APC, and the occurrence of FAP in Family N, are due to a reduced ability of the Y165C and G382D hMYH enzymes to recognize and repair OG:A mismatches.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed1997

GnRH molecular variants in the brain and pituitary gland of pejerrey, Odontesthes bonariensis (Atheriniformes). Immunological and chromatographic evidence for the presence of a novel molecular variant.

Gonadotropin-releasing hormone (GnRH) molecular variants in the brain and pituitary gland of pejerrey, Odontesthes bonariensis (Atheriniformes), were characterized by gradient reverse phase high performance liquid chromatography (RP-HPLC). Eluted fractions were tested in radioimmunoassays with different antisera. The results show that the brain extract contains three forms of GnRH: one is immunologically and chromatographically similar to cIIGnRH (chicken II), and another is similar to sGnRH (salmon). A third GnRH appears to be chromatographic and immunologically different from the nine other known forms of the vertebrate hormone. This is the only variant present in the pituitary gland.

Animals↗

PubMed2026

Genome-wide annotation of human multi-nucleotide variants reveals widespread functional differences from single nucleotide variants.

Multi-nucleotide variants (MNVs) represent a crucial yet underexplored category of genetic variation. Despite previous studies highlighting the prevalence and potential biological impact of MNVs in populations, comprehensive identification and detailed functional annotation of MNVs remain challenging. Here, we develop MNVAnno, a toolbox for rapid identification and annotation of complex MNVs, and utilize it to identify 3,984,258 MNVs from 700,134 human samples, expanding the human MNV list to 8,199,654. Our analysis reveals that MNVs can not only lead to distinct amino acid changes from their constituent single-nucleotide variants, but also significantly impact the function of non-coding regions. Furthermore, through genome-wide association studies, we identify some MNVs associated with multiple cancers, and establish the Human MNV Database to facilitate MNV research. Our study emphasizes the importance of MNV annotation, broadens the human MNV landscape, and opens avenues for exploring genetic variation in phenotypes and diseases.

Humans↗

PubMed1973

Ganglioside patterns and phenotypic characteristics in a normal variant and a transformed back variant of a simian virus 40-induced hamster tumor cell line.

Ganglioside patterns of a cloned Simian virus 40- (SV40) induced hamster tumor cell (Cl(2)TSV(5)-S), its normal variant (Cl(2)TSV(5)-R) which are Cl(2)TSV(5)-S gradually adapted to grow in the presence of 2 microg/ml actinomycin D and exhibit certain normal phenotypic characteristics, and its back variant (Cl(2)TSV(5)-RR), which are Cl(2)TSV(5)-R cells grown in the absence of actinomycin D for more than 60 passages and which exhibit greater phenotypic similarity to Cl(2)TSV(5)-S cells, have been analyzed. All three cell lines contain N(acetylneuraminyl) galactosylglycosyl ceramide (hematoside, GM(3)), N-acetylgalactosaminyl (N-acetylneuraminyl) galactosylglucosyl ceramide (GM(2)), and a higher ganglioside tentatively identified as disialohematoside. However, Cl(2)TSV(5)-R have more GM(2) than Cl(2)TSV(5)-S whereas Cl(2)TSV(5)-RR contain an intermediate amount of GM(2). The amount of GM(2) is correlative with the activity of UDP-N-acetylgalactosamine: hematoside N-acetylgalactosaminyl transferase in the extract of the three cell lines and with their agglutination by wheat germ agglutinin.

Animals↗

PubMed2001

Disparate response of wild-type and variant forms of LH to GnRH stimulation in individuals heterozygous for the LHbeta variant allele.

There is a common genetic variant of LH due to two amino acid changes in the LHbeta subunit, Trp(8)Arg and Ile(15)Thr. In order to compare the relative activities of wild type (wt-LH) and variant LHbeta (v-LHbeta) genes in LH production and secretion, we performed gonadotrophin-releasing hormone (GnRH) stimulation tests for healthy females (n = 7) and males (n = 10) heterozygous for the v-LHbeta allele. Blood samples were drawn up to 180 min after injection of GnRH. The serum samples were subjected to two immunofluorometric assays, one detecting wt hormone, the other detecting equally both LH types. The wt/total ratio increased significantly (P < or = 0.016) after GnRH injection in males. This indicates that the proportion of wt-LH increases in the circulation in men but not in women, and that women consequently secrete relatively more v-LH. An in-vitro bioassay was performed on 0 and 60 min samples, and the bio/immunoreactivity (B/I) ratio decreased in both sexes (P = 0.010-0.012). This supports the previously reported lower B/I ratio of wt. than v-LH, since wt-LH is expected to accumulate in circulation because of its longer half-life. In conclusion, these findings demonstrate that wt.- and v-LH respond differently to GnRH stimulation in men and women heterozygous for v-LHbeta. These results are in agreement with previously documented differences of the two forms in circulation, as well as with different promoter activities of the two LHbeta alleles.

Adolescent↗

PubMed1979

Thymidine kinase enzyme variants in Physarum polycephalum. Kinetics and properties of the enzyme variants.

Thymidine kinase variants of Physarum polycephalum separated by repeated DEAE-cellulose chromatography have been characterized. The enzyme variants show similar catalytic properties (e.g., substrate specificity, pH optimum) and molecular weights, as judges by their sedimentation in sucrose gradients. However, they differ significantly with respect to pI, inhibition by dTTP and thermostability, and they have slightly different Km values for deoxythymidine as a substrate.

Deoxyribonucleotides↗

PubMed2003

Plasmodium falciparum infection elicits both variant-specific and cross-reactive antibodies against variant surface antigens.

Naturally acquired antibodies to Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1), the variant surface antigens expressed on the surface of infected erythrocytes, are thought to play a role in protection against P. falciparum malaria. Here, we have studied the development of antibodies to PfEMP-1 in adult malaria patients living in Rourkela, India, an area with a low malaria transmission rate, and prevalence of antibodies to PfEMP-1 in residents of San Dulakudar, India, a village in which P. falciparum malaria is hyperendemic. Convalescent-phase sera from adult malaria patients from Rourkela agglutinate homologous P. falciparum isolates as well as some heterologous isolates, suggesting that they develop partially cross-reactive antibodies to PfEMP-1 following infection. Adult sera from San Dulakudar agglutinate diverse P. falciparum isolates, suggesting that they have antibodies with wide recognition of diverse PfEMP-1. Mixed-agglutination assays using pairs of P. falciparum isolates confirm the presence of both variant-specific and partially cross-reactive antibodies in convalescent-phase sera from Rourkela and adult sera from San Dulakudar. Analysis of PfEMP-1 sequences suggests a molecular basis for the observed cross-reactivity.

Adult↗

PubMed1994

Isolation and characterization of human immunodeficiency virus type 1 variants infectious to brain-derived cells: detection of common point mutations in the V3 region of the env gene of the variants.

T-cell-line-tropic human immunodeficiency virus type 1 cannot infect CD4-positive, brain-derived cells. We isolated several new variants that readily infected brain-derived cells. Mutation of proline to serine, to alanine, or to threonine in the well-conserved GPGR sequence in the V3 region of the envelope glycoprotein was found in all these variants. This indicates the importance of amino acid sequences at the tip of the V3 region for brain cell tropism of human immunodeficiency virus type 1.

Amino Acid Sequence↗

PubMed1998

The 30-base-pair deletion in Chinese variants of the Epstein-Barr virus LMP1 gene is not the major effector of functional differences between variant LMP1 genes in human lymphocytes.

One group of sequence variants of Epstein-Barr virus is characterized by a 10-amino-acid deletion within the CTAR-2 functional domain of the latent membrane protein, LMP1. A role for this deletion in enhancing the tumorigenicity of the viral oncogene in rodent fibroblasts was recently demonstrated. We examined the effect of this deletion upon LMP1 function in four human lymphoid cell lines by using three natural variants of LMP1: the prototype B95.8 gene and the CAO and AG876 genes, both of which have codons 343 to 352 of the B95.8-LMP1 deleted. These experiments revealed that LMP1-mediated upregulation of CD40 and CD54 was markedly impaired (by 60 to 90%) with CAO-LMP1 compared with B95.8-LMP1. In contrast, the function of AG876-LMP1 was indistinguishable from that of B95.8-LMP1 in two lines and was only slightly impaired in the other two lines. Activation of NF-kappaB by CAO-LMP1 was not impaired in any of the lines; rather, activation of an NF-kappaB reporter by CAO-LMP1 was consistently about twofold greater than the activation with B95.8- or AG876-LMP1. Therefore, while the CAO-LMP1 is functionally distinct from the prototype B95.8-LMP1 in human lymphocytes, the 10-amino-acid deletion appears not to be directly responsible. This conclusion was confirmed by using a B95.8-LMP1 mutant with codons 343 to 352 deleted and chimerae of CAO- and B95.8-LMP1 in which the CTAR-2 domains of these genes were exchanged. Sequences outside the CTAR-2 domain were implicated in the distinct functional characteristics of CAO-LMP1 in human lymphoid cells.

Amino Acid Sequence↗

PubMed1987

Transferrin variants in Japan and New Zealand. Report of an unusually sialyzed TF variant.

The genetic polymorphism of transferrin (TF) was studied in 2,167 Japanese individuals and in 448 New Zealanders. The three TF C subtypes were identified, but TF C3 was absent from Japanese populations. In addition, three TF B and six TF D variants were observed, each of which occurred either in Japanese or in New Zealanders. Stepwise removal of N-acetyl-neuraminic acid (NANA) with neuraminidase revealed that the most cathodal variant TF DShinnanyo found in a Japanese family was characterized by having only two NANA residues.

Gene Frequency↗

PubMed1997

Recombinant staphylokinase variants with altered immunoreactivity. IV: Identification of variants with reduced antibody induction but intact potency.

BACKGROUND: The thrombolytic potency and antibody induction of selected variants of recombinant staphylokinase (SakSTAR), including SakSTAR(K74) with Lys74, SakSTAR(E75) with Glu75-, SakSTAR(EER) with Glu38, Glu75, and Arg77, and SakSTAR(K74ER) with Lys74, Glu75, and Arg77 replaced by Ala, were studied. METHODS AND RESULTS: In rabbits, SakSTAR(74) and SakSTAR(EER) elicited significantly less circulating neutralizing activity than SakSTAR and SakSTAR(E75) (P = .005 and P = .0002 versus SakSTAR, respectively). In baboons, SakSTAR(K74) induced significantly fewer antibodies than wild-type SakSTAR (P < .05). Intra-arterial administration in patients with peripheral arterial occlusion of SakSTAR(K74) (n = 11) or SakSTAR(K74ER) (n = 6) induced significantly fewer circulating neutralizing antibodies [median values and interquartile ranges, 20 (3.8 to 26) and 2.4 (0.2 to 59) micrograms compound neutralized/mL plasma after 3 to 4 weeks (P = .01 and P = .035 versus SakSTAR, respectively)] than SakSTAR (n = 9) [median value and interquartile range, 93 (24 to 110) micrograms compound neutralized/mL plasma]. Overt neutralizing antibody induction (> 10 micrograms compound neutralized/mL plasma) occurred in all 9 patients given wild-type SakSTAR, in 6 of the 11 SakSTAR(K74ER) patients (P = .038 versus SakSTAR), and in 2 of the 6 SakSTAR(K74ER) patients (P = .011 versus SakSTAR). CONCLUSIONS: SakSTAR(K74), a variant of recombinant staphylokinase with a single substitution of Lys74 with Ala, and SakSTAR(K74), with Lys74, Glu75, and Arg77 substituted with Ala, have intact thrombolytic potencies but induce significantly less antibody formation in patients.

Adult↗

PubMed1998

Evidences for an allelic variant of the human LC/CG receptor rather than a gene duplication: functional comparison of wild-type and variant receptors.

Two different human LH receptor sequences have been published, differing by a six-base pair insertion encoding Leu-Gln at position 55-60. It has recently been proposed that this would reflect the existence of two LH receptor loci in the human genome. The present results demonstrate that both sequences exist as allelic variants in the Caucasian population. Allelic frequency of"LQ variant" and "wild-type" (alphaLQ) allele are 0.26 and 0.74 respectively. In contrast, the LQ allele is virtually absent from the Japanese population. Functional characterization of both alleles by transient expression in COS-7 cells did not reveal any difference between the two receptors, neither for cell surface expression nor for cAMP production and sensitivity to hCG/LH.

Alleles↗

PubMed1993

Usefulness of HPLC methodology for the characterization of combinations of the common beta chain variants Hbs S, C, and O-Arab, and the alpha chain variant Hb G-Philadelphia.

We have analyzed the blood samples from seven members of two families that contained mixtures of different hemoglobin types due to the simultaneous presence of different beta chain variants and the alpha chain variant Hb G-Philadelphia. The methods used were isoelectrofocusing and cation exchange high performance liquid chromatography for the separation of the hemoglobin components, and reversed phase high performance liquid chromatography for that of the various alpha and beta chains; the chromatographic procedures also provided quantitative data. Application of these fast and simple high performance liquid chromatographic methods greatly aided in defining the different hemoglobinopathies that were present in these persons, including an additional alpha-thalassemia-2 heterozygosity or homozygosity.

Adult↗

PubMed1999

Two new alpha chain variants: Hb Boghé [alpha58(E7)His-->Gln, alpha2], a variant on the distal histidine, and Hb CHarolles [alpha103(G10)His-Tyr, alpha1].

The present paper reports two new alpha-globin chain variants: Hb Boghé [alpha58(E7)His-->Gln, alpha2] and Hb Charolles [alpha103(G10)His-->Tyr, alpha1]. Hb Boghé was found in a 12-month-old girl who was treated for malignant histiocytosis at 9 months of age and received a bone marrow transplant from her sister. Hb Boghé was undetectable by isoelectrofocusing and high performance liquid chromatography of hemoglobins. It was only revealed by polyacrylamide gel electrophoresis of globin chains in the presence of urea-Triton X-100 and accounted for 10% of the total hemoglobin. Hb Charolles was detected in a 46-year-old patient who presented with microcytosis and hypochromia. It was easily detected by isoelectrofocusing and high performance liquid chromatography. Hb Charolles accounted for 11% of the total hemoglobin. Characterization of the two hemoglobin variants was achieved by DNA and restriction enzyme analyses. Oxygen equilibrium curves measured on whole blood with Hb Boghé were normal. DNA sequencing revealed the association of Hb Charolles with a common mutation of the alpha2 polyadenylation site: AATAAA-->AATAAG.

Amino Acid Substitution↗

PubMed1999

Cribriform-morular variant of papillary carcinoma: a distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma?

We describe herein four cases of an unusual sporadic thyroid tumor that shares the morphologic features of a distinctive follicular cell neoplasm previously proposed as a feasible indicator of familial adenomatous polyposis. We also review five other similar cases reported in the literature. All of the nine patients were young women, aged 16 to 30 years. Grossly, the neoplasms measured 1.5 to 5.6 cm; they were solid and solitary, except one case, which showed two tumor nodules, one in each lobe. Histologically, the lesions were encapsulated, and they exhibited an intricate blending of cribriform, follicular, papillary, trabecular, and solid patterns of growth, with morular (squamoid) areas. Cribriform structures were prominent, being formed by anastomosing bars and arches of cells in the absence of intervening fibrovascular stroma. Follicular areas were usually devoid of colloid, and the papillae were lined by columnar cells. There were focal areas of trabecular arrangement reminiscent of hyalinizing trabecular adenoma. The tumor cells were cuboidal or tall, with frequent nuclear pseudostratification and abundant eosinophilic-to-oxyphilic cytoplasm. The nuclei were usually hyperchromatic, but nuclear grooves, pale or clear nuclei, and intranuclear cytoplasmic inclusions were variably present. Morules with peculiar nuclear clearing caused by biotin accumulation were scattered in the tumors. Vascular and/or capsular invasion were noted in all of the cases except one, and lymph node metastasis was found in two cases. Immunohistochemical stains showed reactivity for thyroglobulin, epithelial membrane antigen, cytokeratins (including 34betaE12), vimentin, estrogen and progesterone receptors, bcl-2, and Rb proteins. Follow-up in seven cases showed that all of the patients were alive with no evidence of disease at 1 to 13 years after diagnosis. Thus, the behavior of this variant seems to be similar to that of conventional papillary carcinoma Because of the distinctive histologic features, we propose naming this tumor the cribriform-morular variant of papillary carcinoma.

Adenomatous Polyposis Coli↗

PubMed1999

Epithelioid variant of pleomorphic liposarcoma: a study of 12 cases of a distinctive variant of high-grade liposarcoma.

We describe 12 patients with a distinctive variant of pleomorphic liposarcoma that histologically shows epithelioid features and focally resembles a solid carcinoma. The tumors occurred in nine men and three women (median age, 63 yr; range, 40-78 yr). Five tumors were in the thigh, two in the chest wall, two in the axilla, and one each in the retroperitoneum, groin, and calf. Most were 15 to 20 cm in maximal diameter. They consisted of sheets of epithelioid-appearing cells with ample, variably eosinophilic cytoplasm, often showing a honeycomb-like pattern of cell borders and little if any collagenous extracellular matrix. Their histologic features often resembled those of renal clear cell carcinoma or adrenal cortical carcinoma, but all showed evidence of adipocytic differentiation, and five also showed focal spindle cell components. One patient whose tumor in the thigh had been originally diagnosed as metastatic renal carcinoma had undergone nephrectomy without a finding of a kidney tumor. All of the cases were positive for vimentin; 6 of 11 cases were positive for S-100 protein, usually focally; 5 of 11 were focally positive for keratins; and all were negative for epithelial membrane antigen, muscle actins, desmin, and CD34. High mitotic activity (mean, 42 mitotic figures per 10 high power fields) and high MIB-1-positive proliferative fraction (>30%) were seen in all of the cases, and nuclear p53 immunoreactivity was detected in five of seven cases. Of the eight patients with complete follow-up, five died of disease (median survival, 6 mo), two died of unrelated causes 10 and 18 years later, and 1 was alive and well 24 years later. The epithelioid variant of pleomorphic liposarcoma is a high-grade tumor that must be distinguished from malignant epithelial tumors, especially in view of the keratin immunoreactivity of some of these neoplasms.

Adult↗

PubMed2000

The proportion of hybrid heterodimers in homozygous or doubly heterozygous beta chain variant hemoglobinopathies associated with alpha chain hemoglobin variants.

Four alpha genes exist on chromosome 16, but one or more of these genes can be deleted in association with Hemoglobin (Hb)G-Philadelphia in cis to alpha-thalassemia-2 in African-Americans. Therefore, the proportion of HbG-Philadelphia in HbG heterozygotes is trimodal at about 25% for alphaGalpha/alpha alpha, 33% for alphaG-/alpha alpha, and 50% for alphaG-/alpha alpha in patients with HbA. Those who are homozygous or doubly heterozygous for beta chain variants (betaX2 or betaXbetaY) have neither HbA nor the alpha chain variant (alphaX2 betaA2), but have hybrid heterodimers (alphaX2 betaX2). The proportion of hybrid heterodimers here should also be trimodal mirroring alpha gene status. Eleven patients were identified: 4 with Hb SSG, 3 with Hb SCG, and 1 each with Hb OCG, HbSSMontgomery, HbSSChicago, and HbSSBourmedes. Heterodimer proportions were: 43.3 +/- 1.5, 33.5 +/- 2.3, and 15.8 +/- 1.1% for 2, 3, and 4 respective alpha genes which had been studied in 8/11 of the patients (r = 0.98), implying that the prime determinant of the proportion of hybrid heterodimers in this patient group is the number of functional alpha genes.

Dimerization↗