Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “allele variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 19 recordsLinked to original sources
PubMedDate not supplied

[Switch in the synthesis of IgM--IgG antibodies. I. Ratio of allelic variants of light rat immunoglobulin chains in antilactoside antibodies of different classes].

Ratio of allelic variants was studied of the rat immunoglobulin light chains in IgM and IgG fractions of anti-lactoside antibodies isolated from the sera of immune heterozygous rats (WAGXMSU)F1 and (AugustXMSU)F1. For MSU rat strain, RL1 allelic variant of light chains is typical whereas WAG and August strains possess the RL2 variant. Anti-lactoside antibodies isolated from sera of F1 rats were separated into high affinity and low affinity fractions. Thereafter each fraction was divided into IgG and IgM classes and each preparation was tested for the content of the molecules of the antibodies with light chains of RL1 and RL2 type. It has been shown that the ratio of allelic variants coincides in IgM and IgG antibody fractions. It follows from this fact that the IgG switch of antibody synthesis may process in the same cell during development of the given population of antibody-producing cells.

Alleles↗
PubMed1978

The number of antibody-producing clones as revealed by the distribution of allelic variants of immunoglobulin light chains.

A new method of evaluation of the number of clonal precursors of antibody-producing cells based on the phenomenon of allelic exclusion is proposed. The distribution of the allotypes of specific antibodies in the population of heterozygous F1 hybrids depends on the number of clonal precursor cells. The smaller the number of precursors, the larger the variance of the distribution. The frequency of clones producing antibodies to the azobenzoate hapten (approximately 10(-8) after first and approximately 10(-9) after second and third immunizations) in (MSU X August)F1 rats calculated in the present work is in reasonable agreement with the data obtained (for other haptens) by limiting dilution cloning assays. The difference in the numbers of anti-hapten and anti-carrier clones is discussed. The numbers of IgM and IgG-synthesizing clones are calculated from the distributions of the allelic variants of corresponding rat antibodies to lactoside. The data suggest the existence of distinct IgG precursors which contradicts the hypothesis of IgM-IgG switch within the clones only.

Alleles↗
PubMed2026

Identification of a Functional CYP2C8 Variant Allele that Alters Splicing, Reduces Protein Expression, and Increases Drug Exposure.

This study investigated genetic determinants of the pharmacokinetics of the CYP2C8 index drugs repaglinide and gemfibrozil, and their interaction in healthy participants. Sequencing data from a study with montelukast revealed a novel functional CYP2C8 allele (rs2071426, CYP2C8*19), predicted to create an intronic splice donor site. In human liver samples, CYP2C8*19 associated with transcript-specific changes in CYP2C8 mRNA expression, reduced CYP2C8 protein expression, and decreased enzyme activity. Consistently, participants with the CYP2C8*19/*19 genotype had 45% greater area under the plasma repaglinide concentration-time curve from time zero to infinity (AUC0-&#x221e;) than participants with CYP2C8*1/*1 (P&#x2009;=&#x2009;1.6&#x2009;&#xd7;&#x2009;10-4). Participants with CYP2C8*1/*3 had 26% smaller AUC0-&#x221e; (P&#x2009;=&#x2009;0.0033) and those with CYP2C8*1/*4 had 51% greater AUC0-&#x221e; (P&#x2009;=&#x2009;8.2&#x2009;&#xd7;&#x2009;10-4). The fold increase in repaglinide AUC0-&#x221e; caused by gemfibrozil was 36% (P&#x2009;=&#x2009;1.3&#x2009;&#xd7;&#x2009;10-4) smaller in CYP2C8*19/*19 participants than in CYP2C8*1/*1 participants. In a genome-wide association study (GWAS), SLCO1B1 c.521&#x2009;T>C (rs4149056) associated with increased repaglinide AUC0-&#x221e; (P&#x2009;=&#x2009;4.5&#x2009;&#xd7;&#x2009;10-15; n&#x2009;=&#x2009;172) and SLCO1A2 variants associated with decreased AUC0-&#x221e; (P&#x2009;<&#x2009;10-8). In a GWAS of repaglinide after gemfibrozil pretreatment, SLCO1C1 variants associated with decreased AUC0-&#x221e; (P&#x2009;<&#x2009;1.6&#x2009;&#xd7;&#x2009;10-8; n&#x2009;=&#x2009;66). Participants with the poor function SLCO1B1 genotype showed a 32% smaller fold increase in repaglinide AUC0-&#x221e; following gemfibrozil than participants with the normal function SLCO1B1 genotype (P&#x2009;=&#x2009;0.0045). This study characterizes CYP2C8*19 as a novel decreased function allele and shows that CYP2C8 and SLCO1B1 genotypes affect the gemfibrozil-repaglinide interaction.

Humans↗
PubMed2023

Spontaneous allelic variant in deafness-blindness gene Ush1g resulting in an expanded phenotype.

Relationships between novel phenotypic behaviors and specific genetic alterations are often discovered using target-specific, directed mutagenesis or phenotypic selection following chemical mutagenesis. An alternative approach is to exploit deficiencies in DNA repair pathways that maintain genetic integrity in response to spontaneously induced damage. Mice deficient in the DNA glycosylase NEIL1 show elevated spontaneous mutations, which arise from translesion DNA synthesis past oxidatively induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting and circling. Mapping of the mutation that conferred these behaviors showed the introduction of a stop codon at amino acid 4 of the Ush1g gene. Ush1gbw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cell's kinocilial links. Consistent with other Usher type 1 models, Ush1gbw/bw mice had no substantial retinal degeneration compared with Ush1gbw /+ controls. In contrast to previously described Ush1g alleles, this new allele provides the first knockout model for this gene.

Mice↗
PubMed2023

Bi-allelic ATG4D variants are associated with a neurodevelopmental disorder characterized by speech and motor impairment.

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

Journal Article↗
PubMed1978

The nomenclature of properdin factor B allotypes.

In a comparative study the presently known eleven allotypes of properdin factor B (Bf) were examined. Bf polymorphism consists of the two common alleles F and S, the two less common alleles F 1 and S 1 and seven further rare alleles. A variant designation has been proposed according to their relative electrophoretic mobility in comparison to the migration difference between the S and F 1 band. There rare variant alleles were redesignated: F 1.55, SO.45 and SO.7, which previously had been described as F 1.6, S 0.8 and S 1, respectively. Conversion studies did neither reveal variant mobility in the Bb nor in the Ba fragment of factor B in three of the rare alleles. This finding confirms the earlier report on one of the variants, possibly suggesting the existence of a so far unknown third clearing fragment.

Alleles↗
PubMed1978

Malate dehydrogenase types in the Asian-Pacific area, and a description of new phenotypes.

A survey of more than 21 000 haemolysates from blood samples collected in various parts of south and southeast Asia, Australasia and the Western Pacific and examined in this laboratory has revealed several new alleles controlling variants of sMDH; in addition, further information has been provided on the distribution of sMDH3 in New Guinea. Two of the variant alleles, sMDH3 and sMDH6, achieve polymorphic frequency in various populations. sMDH3 is widely distributed in New Guinea, with highest frequencies in the Eastern Highlands. The pattern of its distribution suggests the mutant arose originally in a Papuan-speaking population. So far, sMDH6 has been detected only in Micronesians from a number of islands in the Carolines. A single example of another new variant, sMDH 5-1, and two examples of a slow variant, sMDH 7-1, were detected in samples from Iran and Singapore, respectively. No examples of mMDH variants were found in a total of 652 placental extracts from Papua New Guinea and Australia.

Australia↗
PubMed2026

AAV-mediated CBLN1 replacement rescues hereditary ataxia caused by bi-allelic CBLN1 variants.

Cbln1 is a secreted synaptic organizer required for parallel fiber-Purkinje cell (PF-PC) synapse integrity, climbing fiber (CF) refinement, and cerebellar motor learning but has not previously been implicated in human disease. We identified bi-allelic CBLN1 missense variants (A63P and Y112C) in two unrelated families with early-onset cerebellar ataxia accompanied by oculomotor abnormalities, cerebellar atrophy, and variable cognitive delay. In heterologous cells, both variants showed reduced steady-state protein abundance, impaired maturation through the early secretory pathway, and little or no detectable secretion, resulting in markedly reduced extracellular CBLN1 availability. Consistently, cerebellar granule cells expressing CBLN1-Y112C failed to induce excitatory synapses onto glutamate receptor &#x3b4;2 (GluD2)-expressing cells in vitro. A knockin mouse harboring Y112C lacked synaptic Cbln1 and recapitulated key features of Cbln1 deficiency, including disrupted PF-PC synapse organization, persistent CF multi-innervation, impaired PF-PC transmission, and long-term depression, and deficits in motor coordination and oculomotor learning. Notably, systemic delivery of an astrocyte-targeted adeno-associated virus expressing wild-type CBLN1 in adult mutant mice restored synaptic CBLN1 localization, cerebellar synaptic function, plasticity, and behavior. These findings establish CBLN1 deficiency as a cause of hereditary ataxia and identify extracellular CBLN1 replacement as a therapeutic strategy for a reversible cerebellar synaptopathy.

CBLN1↗
PubMed2025

Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL.

Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

Humans↗