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At least 343 records · Page 19Linked to original sources
PubMed2026

Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity.

Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor condition characterized by the expansion of mutant hematopoietic stem and progenitor cell (HSPC) clones that increases the risk of hematologic malignancies. Although genome-wide association studies have identified multiple non-coding loci associated with CHIP susceptibility, their mechanisms remain unclear. We hypothesized that CHIP risk variants alter enhancer activity in HSPCs. To test this, we screened 1,374 non-coding variants from 51 CHIP-associated loci using a Massively Parallel Reporter Assay (MPRA) in the CD34+ fraction of MUTZ-3 cells. We identified 87 regulatory variants across 32 loci. Targeted genome editing in hematopoietic cells and complementary reporter assays in primary human HSPCs validated enhancer activity for variants regulating NKD2, FLT3, and MSI2. Functional studies demonstrated that increased MSI2 expression, modeling the effect of the CHIP risk allele, promotes clonal expansion of TET2-deficient HSPCs, providing a mechanistic link between inherited non-coding variation and CHIP clonal expansion.

Journal Article↗
PubMed2001

The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.

BACKGROUND: Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene. MATERIALS AND METHODS: The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects. RESULTS: No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30.6 +/- 0.9 kg m(-2) (mean +/- SD) in subjects with the C/G genotype and 24.8 +/- 4.6 in subjects with the C/C genotype, P = 0.012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70.1 +/- 14.7 vs. 56.7 +/- 14.2 micromol kg(-1) min(-1), P = 0.014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4.51 +/- 1.12 vs. 5.17 +/- 1.28 mmol L(-1), P = 0.049), but not in women. CONCLUSIONS: The HSL gene is not a major gene for FCHL. However, the - 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.

Adult↗
PubMed1997

Cloning and characterization of human cDNAs encoding a protein with high homology to rat intestinal development protein OCI-5.

We constructed a lambda complementary DNA expression library from the mitoxantrone-resistant human gastric carcinoma cell line EPG85-257RNOV. The library was screened by differential hybridization (resistant cell line against non-resistant cell variant). By this procedure we found five independent cDNA clones representing one single gene that has much higher expression in the mitoxantrone-resistant cell line EPG85-257RNOV than in the non-resistant variant EPG85-257P. One of the cDNA clones (MXR7) contains a complete open reading frame (ORF) encoding a 580-amino acid polypeptide. Amino acid and nucleotide sequence analysis revealed that this gene codes the human variant of a rat intestinal development protein OCI-5.

Amino Acid Sequence↗
PubMed1999

Mutational analysis of the proopiomelanocortin gene in Caucasians with early onset obesity.

OBJECTIVE: Mutations in the human gene encoding the polyhormone peptide proopiomelanocortin (POMC) are associated with obesity in rare cases and the gene co-localizes with a reported quantitative trait loci (QTL) for variations in circulating leptin levels and fat mass on human chromosome 2p21. In this study we have used polymerase chain reaction (PCR) and single strand conformation polymorphism (SSCP) analysis, to test whether variations in the human POMC gene are associated with human obesity. DESIGN AND SUBJECTS: Primary mutational analysis was performed on the coding region of the POMC gene and 500 bp of the putative promoter region, by single strand conformational analysis and sequencing, in 56 subjects with juvenile onset obesity (body mass index (BMI) > or = 31 kg/m2 at the draft board examination). The prevalence of two polymorphisms were further studied in 156 obese and 205 control subjects, and in a population based cohort of 380 extensively characterized young healthy subjects. RESULTS: We have identified a total of six gene variants, five were silent nucleotide substitutions (No51(promoter) g-->c, No670(5'UTR)g-->a, No4512(codon6)c-->t Cys/Cys, No7726(codon116)c-->t Leu/Leu) of which one was prevalent (No8246(3'UTR)c-->t) and one variant changed an amino acid (No8086(codon236)g-->c Arg/Gln). The amino acid substitution was only seen in one subject. Comparing the prevalence of the frequent No8246 silent polymorphism, in an association study comprising 156 subjects with juvenile onset obesity and 205 randomly sampled control subjects (mean BMI 23.5+/-4.7 kg/m2), did not show any relationship to obesity. Also, comparing the prevalence of a known 9bp insertion/deletion variant in the coding region of the gene between obese and lean, showed no association to obesity. Furthermore, analyzing a population based cohort of 380 young healthy Caucasians for the prevalent 3'UTR polymorphism as well as the 9 bp insertion/deletion variant did not show any association to deviations in body fat contents or fasting serum leptin concentrations. CONCLUSION: In conclusion, it is unlikely that variations in the coding region and the putative promoter of the POMC gene are a major cause of juvenile onset human obesity.

3' Untranslated Regions↗
PubMed1998

Structural and functional analysis of the porcine secretory carrier membrane protein 1 gene (SCAMP1).

The secretory carrier membrane proteins (SCAMPs) are highly conserved integral vesicle membrane components of the post-Golgi secretory and endocytic pathways. We have isolated and characterized the porcine SCAMP1 cDNA and gene coding for a variant of the SCAMP family. The SCAMP1 cDNA has a length of 3827 bp including a 133-bp 5' and 2701-bp 3' untranslated region. The mRNA has an open reading frame of 1014 nt coding for a protein of 338 amino acids with a calculated molecular mass of 37.9 kDa and a pI of 7.9. The porcine SCAMP1 is 97.04% identical with the human and rat paralogs, respectively. The SCAMP1 gene consists of nine exons with sizes ranging from 78 to 2842 bp and spans at least 70 kb of genomic DNA on porcine Chromosome (Chr) 2q21-q22. The promoter of the SCAMP1 gene is TATA-box-less, and transcription starts at a G-nucleotide 133 nt upstream the start codon.

Amino Acid Sequence↗
PubMed1999

Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences.

The chemokine receptor gene, CCR5, has become a central theme in studies of host genetic effects on HIV-1 pathogenesis ever since the discovery that the CCR5 molecule serves as a major cell surface co-receptor for the virus. A growing number of genetic variants within the coding and 5' regulatory region of CCR5 have been identified, several of which have functional consequences for HIV-1 pathogenesis. Here we review the CCR5 literature describing CCR5 polymorphism and the functional ramifications that several of these variants have on HIV-1 infection and progression to AIDS. The multiplicity of CCR5 genetic effects on HIV-1 disease underscores the critical importance of this gene in controlling AIDS pathogenesis and provides the logic for develop-ment of therapeutic strategies that target the interaction of HIV-1 envelope and CCR5 in HIV-1 associated disease.

Genetic Variation↗
PubMed1999

A new amyloidogenic transthyretin variant, [D38A], detected by electrospray ionization/mass spectrometry.

A new variant of transthyretin (TTR) was detected by mass spectrometry (MS) in a 63-year-old Japanese female patient suffering from amyloidosis. TTR was analyzed by 2-dimensional liquid chromatography coupled with electrospray ionization MS. Variant TTR showed extra peaks in addition to normal TTR peaks. The extra peaks were about 44 Da smaller than normal TTR peaks, and the abundance of variant peaks showed about 80% of the corresponding normal free and adduct peaks. Direct genomic DNA sequencing of TTR exon 2 showed both adenine and cytosine in the position corresponding to the second base of codon 38. This codes for a variant alanine (GCT) as well as the normal aspartic acid (GAT), indicating that the case is heterozygous for the substitution, [D38A].

Amyloid↗
PubMed1998

Expression of estrogen receptor beta messenger RNA variant in breast cancer.

Estrogen receptor (ER) beta is expressed in a number of tissues, including the breast. We have recently shown that ER-beta mRNA is regulated by estradiol (E2) and that antiestrogens antagonize E2 induction of ER-beta mRNA. Here, we identify by reverse transcription-PCR and by the RNase protection assay a mRNA coding for a variant of ER-beta that is coexpressed with wild-type ER-beta in the ER-alpha-negative, estrogen-independent breast cancer cell line MDA-MB-231 and in malignant breast tumor specimens. In contrast, this variant was not seen in the tested normal breast tissue. Sequence analysis of the ER-beta variant PCR product revealed the absence of 139 bp within the hormone-binding domain. This ER-beta deletion corresponds precisely to the entire exon 5 of ER-alpha. The ER-beta variant protein is predicted to lack part of the hormone-binding domain and may bind E2 with lower affinity than the wild-type ER-beta protein.

Base Sequence↗
PubMed1993

Variants of the MMPI 2-7-8 code type: schizotypal correlates of high point 2, 7, or 8.

Our study sought to evaluate whether examination of the high-point scale among subjects with a 2-7-8 parent configuration on the MMPI could assist in the identification of individuals with schizotypal features. Additionally, this study compared male 2-7-8 subjects to female 2-7-8 subjects to determine whether gender mediates endorsement of items associated with these features. Subjects (N = 106) who produced a 2-7-8 parent profile were subdivided according to high point (2, 7, or 8), and the three subgroups were subsequently compared on other self-report measures associated with schizotypal attributes. Subgroup comparisons revealed that the High 8 and High 2 groups produced a pattern of responding consistent with schizotypal characteristics. In contrast, the at-risk status of the High 7 group appears doubtful. Comparisons based on gender generally revealed no differences among female and male 2-7-8 subjects.

Adolescent↗
PubMed2002

Analysis of the relationship between mannose-binding lectin (MBL) genotype, MBL levels and function in an Australian blood donor population.

The mannose-binding lectin (MBL) pathway of complement activation is an important component of innate host defence. Numerous studies have described associations between the MBL genotype, MBL levels and disease susceptibility. However, genotyping and quantitative assays used in these studies have frequently been limited, and comprehensive data examining the interaction between structural and coding MBL genetic variants, MBL antigenic levels and MBL functional activity are lacking. Such data may be important for accurate planning and interpretation of studies of MBL and disease. This study has examined MBL in a cohort of 236 Australian blood donors. Five MBL promoter and coding single nucleotide polymorphisms were genotyped using polymerase chain reaction-sequence-specific priming (PCR-SSP). Plasma levels of MBL antigen were quantified using a double-antibody enzyme-linked immunosorbent assay (ELISA), and functional MBL levels were quantified using a mannan-binding assay. Activation of the complement pathway by MBL was measured in a C4-deposition assay. Significant associations were found between both coding and promoter polymorphisms and MBL antigenic and functional levels. There was significant correlation between the results of MBL double-antibody, mannan-binding and C4-deposition assays. Comprehensive MBL genotyping and functional MBL quantitation using mannan-binding and C4-deposition assays have the potential to be highly informative in MBL disease association studies.

Australia↗
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↗