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At least 523 records · Page 29Linked to original sources
PubMed2004

Pharmacogenetics of tipifarnib (R115777) transport and metabolism in cancer patients.

The purpose of this study was to perform exploratory relationships between the pharmacokinetics of the farnesyl transferase inhibitor, tipifarnib (R115777, Zarnestra) and allelic variants of genes coding for ATP binding-cassette transporters and drug-metabolizing enzymes. Twenty-eight patients with advanced solid tumors were treated with tipifarnib administered orally at a dose of 200 or 300 mg. Blood samples were collected for pharmacokinetics and genotyping of 10 variants in genes encoding P-glycoprotein (ABCB1), cytochrome P450 isozymes CYP3A4 and CYP3A5, and UDP glucuronosyltransferase isozyme UGT1A1. The homozygous T -allele of ABCB1*8 (1236C > T ) was associated with a trend for a higher area under the curve of tipifarnib as compared to patients with only one or no variant alleles [mean (+/-SD), 5,303 +/- 1,620 ng.h/mL vs. 3,619 +/- 1,275 ng.h/mL; P = 0.047). No statistically significant differences were observed with any other genetic variant ( P > 0.15). Overall, this study indicates that ABCB1 genotype might be correlated with tipifarnib pharmacokinetics, although considerable overlap in exposure measures between genotype groups was observed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Lack of SCN1A mutations in familial febrile seizures.

PURPOSE: Mutations in the voltage-gated sodium channel subunit gene SCN1A have been associated with febrile seizures (FSs) in autosomal dominant generalized epilepsy with febrile seizures plus (GEFS+) families and severe myoclonic epilepsy of infancy. The present study assessed the role of SCN1A in familial typical FSs. METHODS: FS families were selected throughout a collaborative study of the Italian League Against Epilepsy. For each index case, the entire coding region of SCN1A was screened by denaturant high-performance liquid chromatography. DNA fragments showing variant chromatograms were subsequently sequenced. RESULTS: Thirty-two FS families accounting for 91 affected individuals were ascertained. Mutational analysis detected a single coding variant (A3169G) on exon 16. The extended analysis of all family members and 78 normal controls demonstrated that A3169G did not contribute to the FS phenotype. CONCLUSIONS: Our study demonstrated that SCN1A is not frequently involved in common FSs and suggested the involvement of specific FS genes.

Adolescent↗
PubMed1994

Expression of two variants of the human mu opioid receptor mRNA in SK-N-SH cells and human brain.

A partial mu opioid receptor gene was isolated from a human genomic library using a mouse delta opioid receptor cDNA as a probe. Using information from this genomic clone and the published human mu receptor, MOR1, a cDNA was isolated from SK-N-SH mRNA that codes for a variant of the MOR1 mRNA, MOR1A. The presence of MOR1A is also shown in human brain using RT-PCR. MOR1A differs from MOR1 in that the 3' terminal intron has not been removed. An in-frame termination codon is found four amino acids after the 5' consensus splice site, making MOR1A eight amino acids shorter than MOR1. Both receptors show similar ligand binding and coupling to cAMP in CHO-K1 cells. The C-terminal differences between MOR1 and MOR1A could have effects on receptor coupling or receptor transport and localization.

Alternative Splicing↗
PubMed1994

Rare variant (Glu to Lys) in the leucine zipper region of CHOP (GADD153).

CHOP (GADD153) has been shown to be a dominant negative inhibitor of specific transcription factors. Direct sequencing of the gene, amplified from the DNA of a Li-Fraumeni family index case (liposarcoma, breast cancer) revealed a constitutional variant within the coding region. This alteration, though not responsible for the Li-Fraumeni phenotype, resulted in a glutamic acid to lysine switch within the leucine zipper domain, at a residue conserved between CHOP and its potential target molecules and between the human and hamster sequences. The variant created a Taq I restriction fragment length polymorphism (RFLP) facilitating screening. Analysis of 159 breast tumour DNA samples detected two encoding variant alleles (tumour and constitutional DNA).

Adult↗
PubMed2003

Irinotecan pathway genotype analysis to predict pharmacokinetics.

PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2024

Chromosome-scale assembly with improved annotation provides insights into breed-wide genomic structure and diversity in domestic cats.

INTRODUCTION: Comprehensive genomic resources offer insights into biological features, including traits/disease-related genetic loci. The current reference genome assembly for the domestic cat (Felis catus), Felis_Catus_9.0 (felCat9), derived from sequences of the Abyssinian cat, may inadequately represent the general cat population, limiting the extent of deducible genetic variations. OBJECTIVES: The goal was to develop Anicom American Shorthair 1.0 (AnAms1.0), a reference-grade chromosome-scale cat genome assembly. METHODS: In contrast to prior assemblies relying on Abyssinian cat sequences, AnAms1.0 was constructed from the sequences of more popular American Shorthair breed, which is related to more breeds than the Abyssinian cat. By combining advanced genomics technologies, including PacBio long-read sequencing and Hi-C- and optical mapping data-based sequence scaffolding, we compared AnAms1.0 to existing Felidae genome assemblies (20 scaffolds, scaffolds N50 > 150 Mbp). Homology-based and ab initio gene annotation through Iso-Seq and RNA-Seq was used to identify new coding genes and splice variants. RESULTS: AnAms1.0 demonstrated superior contiguity and accuracy than existing Felidae genome assemblies. Using AnAms1.0, we identified over 1.5 thousand structural variants and 29 million repetitions compared to felCat9. Additionally, we identified > 1,600 novel protein-coding genes. Notably, olfactory receptor structural variants and cardiomyopathy-related variants were identified. CONCLUSION: AnAms1.0 facilitates the discovery of novel genes related to normal and disease phenotypes in domestic cats. The analyzed data are publicly accessible on Cats-I (https://cat.annotation.jp/), which we established as a platform for accumulating and sharing genomic resources to discover novel genetic traits and advance veterinary medicine.

Animals↗
PubMed1998

Systematic search for mutations in the 14-3-3 eta chain gene on chromosome 22 in schizophrenics.

The brain-rich 14-3-3 protein regulates synthesis and excretion of bioamine by activating tyrosine and tryptophan hydroxylases, and by exocytosis of catecholamines and serotonin. In humans, at least eight subunits of the 14-3-3 protein family have been isolated. The 14-3-3 eta chain gene is located at 22q12.1 to q13.1, one of the chromosome regions identified as possibly linked to schizophrenia. We systematically searched for nucleotide variants in the coding region, 5' and 3' untranslated region, and in the exon-intron boundaries of the genomic 14-3-3 eta gene in 24 schizophrenics and 24 controls. Two polymorphic sites were found: one in the 5' untranslated region and one in the 3' untranslated region. However, no variants predicting amino-acid alterations were observed. Similar allelic and genotypic distributions for both polymorphisms were found in 308 schizophrenics and 135 controls.

14-3-3 Proteins↗
PubMed2025

In silico prediction of the impact of genomic variations in the small conductance calcium activated potassium channel SK3 structure and function.

The small-conductance calcium-activated potassium channel SK3, encoded by the KCNN3 gene, plays a critical role in regulating dopaminergic neuron (DN) firing patterns by modulating after hyperpolarization currents. SK3 dysfunction has been implicated in neuropsychiatric and neurodegenerative disorders. We analyzed structural and functional consequences of KCNN3 splicing and genetic variation. Alternative splicing variants of the KCNN3 gene were retrieved from the Ensembl database and aligned using T-Coffee, manually inspected and curated. Protein domains were identified with Pfam 35.0, SMART 9.0, and InterPro 98.0, and visualized. An AlphaFold2 model of SK3 full-length protein (UniProt: Q9UGI6) used as reference and structural models of its splicing variants were predicted with ColabFold. Functional domains (S1-S6 transmembrane helices, H5 pore loop, and calmodulin-binding) were defined and superimposed onto the AlphaFold2 reference. Domain integrity was assessed based on completeness of all expected residue indices within each functional region. SNPs and CNVs across all coding KCNN3 splicing variants were analyzed, classified, and filtered to isolate pathogenic variants prioritizing non-synonymous amino acid substitutions. Differential variant impacts across splicing isoforms were assessed by mapping variant positions to individual transcript protein sequences and used to predict functional consequences. Two long and two short splicing variants are known. Short variants lack the motif required for potassium channels. Pathogenic variants result from missense mutations resulting in amino acid substitutions. In all cases, the consequential effects depend on the specific location and role of the amino acid being changed.

SK3 channels↗
PubMed2002

A distinct 5' flanking var gene region regulates Plasmodium falciparum variant erythrocyte surface antigen expression in placental malaria.

The Plasmodium falciparum multigene var family codes for approximately 50 variant adhesive proteins expressed in a mutually exclusive manner at the surface of infected red blood cells (iRBCs). Switching expression of var genes can lead to fundamental changes in the adhesive and antigenic properties of iRBCs. For example, a specific phenotypic switch in adhesion from CD36 to chondroitin sulphate A (CSA) is associated with malaria pathogenesis in pregnant women. The factors and DNA elements that control the expression of a particular member of the var gene family during gestational malaria remains enigmatic. Here, we report that the subtelomeric FCR3 varCSA is expressed under the control of a unique DNA element of 1.8 kb, whereas the other members of the var multigene family are flanked by common regulatory elements. The 5' varCSA-type element is conserved as a single copy in laboratory strains and clinical isolates from Brazil and West Africa and contains two distinct repetitive elements of 150 bp and 60 bp respectively. The 5' varCSA-type sequence tags a var gene in the 3D7 genome that is homologous to the FCR3 varCSA gene. A recombinant DBL gamma domain of this var gene showed specific binding to CSA. This subtelomeric varCSA gene is transcribed in the opposite sense when compared with the usual orientation of telomere-adjacent var genes. This unique arrangement might explain why the varCSA gene is relatively conserved in genetically distinct parasites despite being located in a highly recombinogenic chromosome compartment. The 5' untranslated region (UTR) of the varCSA-type sequence is also transcribed in placental isolates that bind to CSA, illustrating an important role for the unique 5' varCSA-type sequence in the regulation of var genes involved in malaria pathogenesis in pregnant women. However, this promoter is not always found to be transcribing var genes selected for expression of products that bind to CSA in vitro. Our work identifies a sequence tag for the identification of varCSA genes in placental isolates for the first time.

5' Untranslated Regions↗
PubMed1995

Identification of proximal sequence element nucleotides contributing to the differential expression of variant U4 small nuclear RNA genes.

The two U4 genes in the chicken genome code for distinct sequence variants of U4 small nuclear RNA that are differentially expressed during development. Whereas U4B RNA is constitutively expressed, U4X RNA is specifically down-regulated relative to U4B in a tissue-specific manner during development. To investigate mechanisms controlling the differential expression of the U4B and U4X genes, chimeric U4 genes were constructed and their transcriptional activities assayed by injection into Xenopus oocytes or by transfection of CV-1 cells. The proximal regulatory region of the U4B gene and the enhancers of both the U4B and U4X genes functioned efficiently in each expression system. However, the proximal region of the U4X gene was inactive. To localize and identify the responsible nucleotides, reciprocal point mutations were introduced into the U4X and U4B proximal regulatory regions. The results indicate that the U4X gene contains a suboptimal proximal sequence element, and that this results primarily from the identities of the nucleotides at positions -61 and -57 relative to the transcription start site.

Animals↗
PubMed2004

Autonomic nervous system pharmacogenomics: a progress report.

Pharmacogenetics, the inherited basis for interindividual differences in drug response, has rapidly expanded with the advent of new molecular tools and the sequencing of the human genome, yielding pharmacogenomics. We review here recent ideas and findings regarding pharmacogenomics of components of the autonomic nervous system, in particular, neuronal nicotinic acetylcholine receptors, postsynaptic receptors with which the parasympathetic and sympathetic neurotransmitters, acetylcholine (ACh) and norepinephrine, respectively, interact. The receptor subtypes that mediate these responses, M(1-3) muscarinic cholinergic receptors (mAChRs), and alpha(1A,B,D)-, alpha(2A,B,C)-, and beta(1,2,3)-adrenergic receptors (AR), show highly variable expression of genetic variants; variants of mAChRs and alpha(1)-ARs are relatively rare, whereas alpha(2)-AR and beta-AR subtype variants are quite common. The largest amount of data is available regarding variants of the latter ARs and represents efforts to associate certain receptor genotypes, most commonly, single nucleotide polymorphisms, with particular phenotypes (e.g., cardiovascular and metabolic responses). In vitro and in vivo studies have yielded inconsistent results; definitive conclusions are limited. We identify several conceptual and methodological problems with available data: sample size, ethnicity, tissue differences, coding versus noncoding variants, limited studies of haplotypes, and interaction among variants. Thus, although progress has been made in identifying genetic variation that influences drug response fo autonomic nervous system components, we are still at the early stages of defining the most critical genetic determinants and their role in human physiology and pharmacology.

Animals↗
PubMed1994

Insulin receptor substrate-1 variants in non-insulin-dependent diabetes.

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.

Aged↗
PubMed1995

Differential alternative splicing of PACAP receptor in pituitary cell subpopulations.

The capability of rat pituitary cells to express receptors for pituitary adenylate cyclase activating polypeptide (PACAP) and VIP was evaluated by binding studies and measurement of adenylate cyclase activity on whole gland preparations and by reverse transcriptase-polymerase chain reaction (TR-PCR) using specific primers on preparations from isolated cell populations enriched in PRL- and GH-producing cells. Data obtained on whole gland preparations indicated that selective PACAP receptors (PACAP Type I) predominated. The mRNA coding for PACAP Type I and for the non-selective PACAP receptors Type II VIP2 (but not VIP1) were identified. The mRNA coding for four different spliced variants of the PACAP Type I receptor were detected. In PRL producing cells, three variants and the VIP2 mRNA were detected, whereas in GH-producing cells the mRNA coding for the variant having a 28-amino acid insert (termed HOP) in the third intracellular loop was the only present.

Adenylyl Cyclases↗
PubMed2025

Rare pathogenic NR2F2 (COUP-TFII) variants as potential etiological causes in pediatric patients with congenital heart diseases (CHDs).

OBJECTIVES: Congenital heart diseases (CHDs) are complex genetic disorders, and their genetic basis is not yet fully understood. Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TFII) encodes a transcription factor which is expressed at high levels during mammalian development. Few studies have identified heterozygous and rare variants in the NR2F2 gene in individuals with CHD. This study aimed to evaluate the association between pathogenic genetic alterations in NR2F2 with CHD risk. METHODS: A case-control study was conducted on a group of 135 patients (83 boys and 52 girls) with various types of non-hereditary, isolated CHD who were undergoing open-heart surgery. Additionally, 95 matched healthy children without syndromic or isolated heart abnormalities were selected. RESULTS: Using Sanger sequencing, we identified 5 heterozygous single nucleotide variants in exons 2 and 3 of the NR2F2 gene. These variations were novel and not present in any genomic variation databases. Four of the variations were missense mutations (p.Pro159Arg, p.Ser329Phe, p.Qln338Pro, and p.Tyr348Ser) and one was a synonymous variant (p.G361 = ) in the coding region. Importantly, in silico results indicated that the missense variants had pathogenic effects on protein function. Additionally, the missense variants substantially altered the predicted structure of COUP-TFII. CONCLUSION: The results we obtained not only validate the correlation between NR2F2 mutations and CHDs but also have significant potential for guiding new preventive and therapeutic strategies. This could contribute to the advancement of medical interventions in the fields of cardiology and genetics.

Humans↗
PubMed2003

Role of DNA mismatch repair genetic polymorphisms in the risk of childhood acute lymphoblastic leukaemia.

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Genetic variants in the coding regions of the mismatch repair genes MLH1 (Ile-219Val) and MSH3 (Arg-940Glu and Thr-1036Ala) could contribute to an individual's susceptibility as modifiers in leukaemogenesis. To investigate this possibility, we conducted a case-control study on 287 children with ALL and 320 healthy controls both of French-Canadian origin. MLH1 and MSH3 variants, when taken independently, seemed to play little or no role in the aetiology of childhood ALL. However, when the MLH1 genotypes were combined with genotypes previously shown to influence ALL susceptibility, we found that the MLH1 variant Val-219 further increases the risk of GSTM1 null and CYP1A1*2A genotypes [combined odds ratio (OR) = 6.0, P = 0.002] as well as that of CYP2E1*5 (OR = 15.8, P = 0.001). No association was found with MSH3 variants. This study suggests an association of leukaemogenesis in children with both xenobiotic metabolism and DNA repair, and thus points to the effect of environmental exposure.

Adaptor Proteins, Signal Transducing↗
PubMed1997

[The topological structure of the genetic code].

On the basis of the topological concept of the vicinity of the point, graphs of connectedness for four nitrous bases (L and D tetrahedra) and the topological patterns of doublet and triplet genetic codes were constructed. These topological patterns were isomorphic to Boolean hypercubes B4 and B6, respectively. The resultant structures of the genetic code resembled those obtained earlier in terms of the rhombic variant of the genetic code table, which was constructed on the basis of complementarity of the coding doublets. Specifically, both models assumed the following: (1) when two groups of doublets and quartets of triplets that coded for one amino acid or two amino acids each were transformed into each other according to Rumer's rule (C <--> A, G <--> U), they retained C2 symmetry, and (2) single transitions of nitrous bases changed the structures of the encoded amino acids to the minimum possible extent. A possible mechanism for the origin of the genetic code and the possibility of using the characteristics of the obtained structures to develop the algorithm of prediction of the supermolecular protein structure, read genetic "texts", and refine the functions of amino acids as molecular modules are discussed in terms of the results obtained.

Algorithms↗
PubMed1995

Identification of polymorphisms and sequence variants in the human homologue of the mouse natural resistance-associated macrophage protein gene.

The most common mycobacterial disease in humans is tuberculosis, and there is evidence for genetic factors in susceptibility to tuberculosis. In the mouse, the Bcg gene controls macrophage priming for activation and is a major gene for susceptibility to infection with mycobacteria. A candidate gene for Bcg was identified by positional cloning and was designated "natural resistance-associated macrophage protein gene" (Nramp1), and the human homologue (NRAMP1) has recently been cloned. Here we report on (1) the physical mapping of NRAMP1 close to VIL in chromosome region 2q35 by PCR analysis of somatic cell hybrids and YAC cloning and (2) the identification of nine sequence variants in NRAMP1. Of the four variants in the coding region, there were two missense mutations and two silent substitutions. The missense mutations were a conservative alanine-to-valine substitution at codon 318 in exon 9 and an aspartic acid-to-asparagine substitution at codon 543 in the predicted cytoplasmic tail of the NRAMP1 protein. A microsatellite was located in the immediate 5' region of the gene, three variants were in introns, and one variant was located in the 3' UTR. The allele frequencies of each of the nine variants were determined in DNA samples of 60 Caucasians and 20 Asians. In addition, we have physically linked two highly polymorphic microsatellite markers, D2S104 and D2S173, to NRAMP1 on a 1.5-Mb YAC contig. These molecular markers will be useful to assess the role of NRAMP1 is susceptibility to tuberculosis and other macrophage-mediated diseases.

Alleles↗
PubMed2004

Met326Ile aminoacid polymorphism in the human p85 alpha gene has no major impact on early insulin signaling in type 2 diabetes.

Class I alpha phosphatidylinositol (PI) 3-kinase is an important enzyme in the early insulin signaling cascade, and plays a key role in insulin-mediated glucose transport. Despite extensive investigation, the genes responsible for the development of the common forms of type 2 diabetes remain unknown. This study was performed to identify variants in the coding region of p85 alpha, the regulatory subunit of PI 3-kinase. Fibroblasts from skin biopsies from type 2 diabetics and controls were established to address this issue. P85 alpha cDNA was sequenced, and a single point mutation at codon 326 was found. This mutation resulted in a homozygous missense amino acid change Met --> Ile in one subject with type 2 diabetes and heterozygous variant in two other diabetic patients and one with severe insulin resistance. Interestingly, those patients revealed an impaired insulin-mediated insulin receptor substrate (IRS)-1 binding to p85 alpha without any alteration in IRS-2/p85 alpha association. Furthermore, IRS-1, IRS-2, p85 alpha and MAPK protein contents were not significantly changed, and neither were MAPK or Akt phosphorylation. We conclude from our data that this variant may have only minor impact on signaling events; however, in combination with variants in other genes encoding signaling proteins, this may have a functional impact on early insulin signaling.

Diabetes Mellitus, Type 2↗