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At least 415 records · Page 23Linked to original sources
PubMed2000

Mutations in the insulin promoter factor-1 gene in late-onset type 2 diabetes mellitus.

OBJECTIVE: Insulin promoter factor-1 (IPF-1) is a transcription factor expressed in pancreatic beta cells. Following the identification of missense variants in the coding regions of the IPF-1 gene, in subjects selected for a strong family history of type 2 diabetes, the aim of our study was to evaluate the prevalence of these variants in the common form of type 2 diabetes. METHODS: Three variants (C18R, Q59L and D76N) were screened by PCR-RFLP in a group of 296 unrelated French late-onset type 2 diabetic subjects consecutively recruited in a diabetes department of a university hospital, regardless of family history of diabetes. RESULTS: The C18R and Q59L variants were each found in 0.37% of the diabetic patients, and in none of 147 controls. We did not detect the D76N variant, which was the most frequent variant in subjects with a strong family history of diabetes, in patients or controls. CONCLUSIONS: We have observed a combined prevalence of missense variants in the coding region of the IPF-1 gene of around 1%, in unselected patients with the common form of late-onset type 2 diabetes. The prevalence of these variants in subjects with a strong family history of type 2 diabetes had been found to be as high as approximately 6%. These differences in prevalence might be related to differences in the clinical profile of patients, such as age of onset of diabetes and associated obesity, as well as a family history of diabetes.

Age of Onset↗
PubMed2005

Variants of the Drosophila melanogaster Ih-channel are generated by different splicing.

We isolated splice variants of the DMIH cDNA encoding members of the I(h)-channel family from Drosophila melanogaster by means of polymerase chain reaction and homology screening. Splicing at four different sites generates a great variety of different channel transcripts. The variants so obtained code for ion channel proteins with long or short N-termini and variations in the length of the interloop regions between the membrane-spanning domains S3-S4 and S4-S5. The multiple variants of DMIH coded by a single gene thus might form the molecular basis for a variety of I(h)-channels. Functional expression of one of the DMIH variants with a long N-terminus in HEK293 cells produced unitary currents that were preferentially selective for potassium over sodium ions and were activated by hyperpolarizing voltage steps. Cyclic nucleotides shifted the voltage activation curve to more positive membrane potentials. The current kinetics and modulatory influence of cyclic nucleotides resemble closely those of other invertebrate I(h)-channels, but activation by hyperpolarizing voltage steps had a V(1/2) of 123 mV, a more negative value than those of other recombinantly expressed insect I(h)-channels with a short N-terminus.

Alternative Splicing↗
PubMed1986

Mung bean nuclease cleaves preferentially at the boundaries of variant surface glycoprotein gene transpositions in trypanosome DNA.

Telomere-linked genes coding for the variant surface glycoproteins (VSGs) of African trypanosomes have been difficult to clone because their flanking regions frequently lack restriction sites. Therefore, we constructed a genomic DNA library of fragments generated by digestion of purified trypanosome DNA with mung bean nuclease, an enzyme that cleaves before and after genes in Plasmodium falciparum DNA (McCutchan, T. F., Hansen, J. L., Dame, J. B., and Mullins, J. A. (1984) Science 225, 625-628). Southern hybridizations with several gene probes showed that under the appropriate conditions mung bean nuclease produces discrete trypanosome DNA fragments that are as clearly resolved on an agarose gel as restriction fragments. The majority of VSG genes are on fragments of about 1.7 kilobase pairs. To examine the sites of mung bean nuclease cleavage, the insert boundary sequences of eight recombinant clones in the library containing VSG genes were determined. In general, mung bean nuclease cleaved 300-800 base pairs in front of the VSG start codon and within 50 base pairs on either side of the termination codon. These regions also form the boundaries of VSG gene conversion events indicating that the enzyme recognizes, in part, a conformational structure rather than a specific sequence. The analyzed clones included both telomere-linked and interior basic copy VSG genes indicating that the library potentially contains all of the telomere-linked VSG genes in the genome.

Animals↗
PubMed2026

Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.

The genetic architecture of sporadic Early-Onset Alzheimer Disease (sEOAD, onset ≤65 years) remains largely unknown. To assess the de novo mutation (DNM) hypothesis, we performed a nationwide recruitment of 37 novel sEOAD patients-unaffected parents trios. After assessing known monogenic genes, we performed trio-based exome sequencing and jointly analyzed novel trios with 12 previously reported ones. Of these, we selected 16 trios for genome sequencing. We identified three patients with a pathogenic DNM in APP or PSEN1. Then, from the 46 remaining trios, we identified 38 non-synonymous coding DNM and 4 de novo copy number variants (CNVs) in exome data. Four DNM (2 novel, in SPHK2 and DDR1) and bi-allelic inherited variants in two genes affected Alzheimer disease-related genes. No significant burden of rare coding variants in exome/genome data from 5643 EOAD cases and 16097 controls was identified using nested windows centered on each DNM position, at the transcript level. From genome data, one non-coding DNM was predicted to affect splicing in an AD-associated gene, PINX1. Overall, 48% probands carried ≥1 inherited risk factor with odds ratio (OR) > 1.5 and GWAS-defined Genetic Risk Scores (GRS) distribution was more consistent with random distribution than enrichment in higher scores in probands. We confirm that DNMs in known monogenic genes explain sEOAD in a minority of cases, while candidate DNMs in other genes might account for a small proportion of additional cases. The majority of sEOAD patients may have a complex etiology including multiple inherited variants, however, GRS might not explain most of its genetic component.

Humans↗
PubMedDate not supplied

An H1 histone gene from rainbow trout (Salmo gairdnerii).

A 1.7-kbp DNA region from the 10.2-kb cluster containing the five rainbow trout histone genes has been subcloned in pBR322 and completely sequenced. It contains a trout histone H1 gene together with its 5' and 3' flanking sequences. This H1 gene codes for a H1 variant different from the major trout testis H1 previously sequenced by Macleod et al. (1977). Northern blots of total RNA from trout testis, kidney, and liver indicate that this H1 gene is expressed in all three tissues but that the level of H1 mRNA is much higher in testis than in other tissues. The lack of heterogeneity in the sizes and 5' initiation sites of trout H1 mRNAs is surprising in view of the substantial heterogeneity of H1 variant proteins observed previously. The coding sequence of the H1 gene shows strong evidence of repeated partial duplications of a hexapeptide motif of the form Ala.Ala.Ala.Lys.Lys.Pro and of a pentapeptide phosphorylation-site sequence, Lys.Ser.Pro.Lys.Lys, during its evolution. Comparisons are drawn between this gene and the coding sequences of other vertebrate H1 genes from chicken and Xenopus, and a strong homology is seen in the region of amino acids 22-101, which form the hydrophobic "head" of the H1 molecule. The 5' and 3' regulatory signals in the trout H1 are also compared with those of H1 genes from other sequences.

Amino Acid Sequence↗
PubMed1998

On error minimization in a sequential origin of the standard genetic code.

Distances between amino acids were derived from the polar requirement measure of amino acid polarity and Benner and co-workers' (1994) 74-100 PAM matrix. These distances were used to examine the average effects of amino acid substitutions due to single-base errors in the standard genetic code and equally degenerate randomized variants of the standard code. Second-position transitions conserved all distances on average, an order of magnitude more than did second-position transversions. In contrast, first-position transitions and transversions were about equally conservative. In comparison with randomized codes, second-position transitions in the standard code significantly conserved mean square differences in polar requirement and mean Benner matrix-based distances, but mean absolute value differences in polar requirement were not significantly conserved. The discrepancy suggests that these commonly used distance measures may be insufficient for strict hypothesis testing without more information. The translational consequences of single-base errors were then examined in different codon contexts, and similarities between these contexts explored with a hierarchical cluster analysis. In one cluster of codon contexts corresponding to the RNY and GNR codons, second-position transversions between C and G and transitions between C and U were most conservative of both polar requirement and the matrix-based distance. In another cluster of codon contexts, second-position transitions between A and G were most conservative. Despite the claims of previous authors to the contrary, it is shown theoretically that the standard code may have been shaped by position-invariant forces such as mutation and base content. These forces may have left heterogeneous signatures in the code because of differences in translational fidelity by codon position. A scenario for the origin of the code is presented wherein selection for error minimization could have occurred multiple times in disjoint parts of the code through a phyletic process of competition between lineages. This process permits error minimization without the disruption of previously useful messages, and does not predict that the code is optimally error-minimizing with respect to modern error. Instead, the code may be a record of genetic process and patterns of mutation before the radiation of modern organisms and organelles.

Amino Acids↗
PubMed1996

Cotranscription of two RNA coding for the cell adhesion regulator and its variant in Reh leukemia cells.

Human genomic DNA analysis reveals the existence of polymorphisms at the cell molecular adhesion regulator (CMAR) locus. In order to choose between the two possible open frames deduced from the variant sequence, we have sequence both the human 5' non-coding region and the mouse CMAR variant DNA. We found that both mRNA species coexist in human cells.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2006

Functional effects of genetic variants in the 11beta-hydroxylase (CYP11B1) gene.

OBJECTIVE: We previously described an association between the -344C/T 5'-untranslated region (UTR) polymorphism in the CYP11B2 (aldosterone synthase) gene and hypertension with a raised aldosterone to renin ratio (ARR); the same genetic variant is also associated with impaired adrenal 11beta-hydroxylase efficiency. The -344 polymorphism does not seem to be functional, so is likely to be in linkage with variants in CYP11B1 that determine the associated variation in 11beta-hydroxylase efficiency. We therefore aimed to determine whether there is an association between CYP11B1 variants and hypertension and/or an altered ARR. DESIGN AND MEASUREMENTS: We screened 160 subjects divided into four groups, normotensive controls, unselected hypertensive subjects, and hypertensive subjects with either a high (> or = 750) or low ARR (< or = 200), for variants in the coding region of CYP11B1 by single-stranded conformation polymorphism (SSCP) and direct sequencing. The effects of these variants on enzyme function were assessed by conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. RESULTS: Eight novel missense mutations were identified in the CYP11B1 gene that alter the encoded amino acids: R43Q, L83S, H125R, P135S, F139L, L158P, L186V and T196A. In each case they were heterozygous changes. However, no mutations were identified that could account for hypertension and/or a raised ARR. The variants L158P and L83S severely impaired enzyme function while R43Q, F139L, P135S and T196A enzymes resulted in product levels that were approximately 30-50% that of wild-type levels. The variant enzymes H125R and L186V resulted in substrate-specific alterations in enzyme function. H125R decreased conversion of 11-deoxycortisol to cortisol and L186V increased 11-deoxycortisol conversion. Neither had an effect on the conversion of DOC to corticosterone. CONCLUSION: No variants were identified in the coding region of CYP11B1 that could account for hypertension and/or a raised ARR. However, this in vitro study identifies the importance of these affected residues to enzyme function and will inform subsequent studies of structure-function relationships.

Adolescent↗
PubMed1979

The genetic and cytogenetic localization of the three structural genes coding for the major protein of drosophila larval serum.

The alpha, beta and gamma polypeptides that make up Drosophila Larval Serum Protein-1 seem to be coded for by genes that have evolved by duplication of a common ancestral gene. We have found variants of all three polypeptides, and these are variants of the coding sequences. The alpha-chain variant mapped to 39.5 on the X chromosome and to the polytene interval 11A7-11B9. The beta-chain variant mapped to 1.9 on chromosome 2L and to 21D2-22A1. The gamma-chain variant was mapped as 0.13 map units from the tip of chromosome 3L or to --1.41 with respect to ru, which has been defined as 0.0, and to 61A1-61A6.

Animals↗
PubMed2005

Two human ACAT2 mRNA variants produced by alternative splicing and coding for novel isoenzymes.

Acyl coenzyme A:cholesterol acyltransferase 2 (ACAT2) plays an important role in cholesterol absorption. Human ACAT2 is highly expressed in small intestine and fetal liver, but its expression is greatly diminished in adult liver. The full-length human ACAT2 mRNA encodes a protein, designated ACAT2a, with 522 amino acids. We have previously reported the organization of the human ACAT2 gene and the differentiation-dependent promoter activity in intestinal Caco-2 cells. In the current work, two human ACAT2 mRNA variants produced by alternative splicing are cloned and predicted to encode two novel ACAT2 isoforms, named ACAT2b and ACAT2c, with 502 and 379 amino acids, respectively. These mRNA variants differ from ACAT2a mRNA by lack of the exon 4 (ACAT2b mRNA) and exons 4-5 plus 8-9-10 (ACAT2c mRNA). Significantly, comparable amounts of the alternatively spliced ACAT2 mRNA variants were detected by RT-PCR, and Western blot analysis confirmed the presence of their corresponding proteins in human liver and intestinecells. Furthermore, phosphorylation and enzymatic activity analyses demonstrated that the novel isoenzymes ACAT2b and ACAT2c lacked the phosphorylatable site SLLD, and their enzymatic activities reduced to 25%-35% of that of ACAT2a. These evidences indicate that alternative splicing produces two human ACAT2 mRNA variants that encode the novel ACAT2 isoenzymes. Our findings might help to understand the regulation of the ACAT2 gene expression under certain physiological and pathological conditions.

Alternative Splicing↗
PubMed2005

Polymorphic variants on chromosomes probably play a significant role in infertility.

Polymorphic variants on chromosomes are considered 'normal', as heterochromatin has no coding potential and nucleolar organizing regions (NOR) contain genes coding for rRNA. Variants have been reported in infertility and recurrent abortions. With refined molecular techniques, genes for fertility and viability are now thought to reside in heterochromatin. DNA sequence analysis of human chromosome 9 has shown that it is highly structurally polymorphic, with many intrachromosomal and interchromosomal duplications, and contains the largest autosomal block of heterochromatin. Transcriptional activation of constitutive heterochromatic domains of the human genome in response to environmental stress was reported recently. Heat shock triggers the assembly of nuclear stress bodies on the pericentromeric heterochromatin of human chromosomes including chromosome 9. These are characterized by an epigenetic status typical of euchromatic regions. On acrocentric chromosomes, NOR-associated protein count and morphology was reported to separate benign and malignant melanocytic lesions. Hence all variants may not be 'normal'. The present study of karyotyping 842 individuals attending an IVF clinic with primary infertility or repeated miscarriages, showed polymorphic variants in 28.82% of males and 17.19% of females, which was quite high. It is suggested that variants should not be ignored by cytogeneticists. Screening prospective gamete donors for chromosome variants may help enhance the success of IVF.

Chromosomes, Human↗
PubMed2005

Conservation of the RB1 gene in human and primates.

Mutations in the RB1 gene are associated with retinoblastoma, which has served as an important model for understanding hereditary predisposition to cancer. Despite the great scrutiny that RB1 has enjoyed as the prototypical tumor suppressor gene, it has never been the object of a comprehensive survey of sequence variation in diverse human populations and primates. Therefore, we analyzed the coding (2,787 bp) and adjacent intronic and untranslated (7,313 bp) sequences of RB1 in 137 individuals from a wide range of ethnicities, including 19 Asian Indian hereditary retinoblastoma cases, and five primate species. Aside from nine apparently disease-associated mutations, 52 variants were identified. They included six singleton, coding variants that comprised five amino acid replacements and one silent site. Nucleotide diversity of the coding region (pi=0.0763+/-1.35 x 10(-4)) was 52 times lower than that of the noncoding regions (pi=3.93+/-5.26 x 10(-4)), indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and five primates, which yielded an estimated ratio of replacement to silent substitutions (omega) of 0.095 across all lineages. RB1 displayed extensive linkage disequilibrium over 174 kb, and only four unique recombination events, two in Africa and one each in Europe and Southwest Asia, were observed. Using a parsimony approach, 15 haplotypes could be inferred. Ten were found in Africa, though only 12.4% of the 274 chromosomes screened were of African origin. In non-Africans, a single haplotype accounted for from 63 to 84% of all chromosomes, most likely the consequence of natural selection and a significant bottleneck in effective population size during the colonization of the non-African continents.

Animals↗
PubMed1996

Do sequence variants in the major non-coding region of the mitochondrial genome influence mitochondrial mutations associated with disease?

Several different mutations in human mitochondrial DNA (mtDNA) have been associated with disease, but their origins and the basis of the wide phenotypic variability remain to be elucidated. We initially investigated three patients with heteroplasmic disease associated mutations of mtDNA for the presence of cis mutations in the major non-coding region that might influence their origins or pathology. A T --> C transition at nt 16 189 previously identified in one patient with the 3243 G:C mutation was associated with heteroplasmic length variation. Identical length variation was found in patient-derived cybrid lines containing 0-97.5% 3243 G:C. Similarly, heteroplasmic length variation was demonstrated in 2/6 other probands with both the 3243 mutation and the 16,189 polymorphism. The distribution of length variants in probands and in asymptomatic family members was identical in all cases. Thus length variation appears to be independent of the level of 3243 mutant mtDNA and hence probably arose within both 3243 G:C and 3243 A:T mtDNAs. We suggest that the 16,189 polymorphism reflects a predisposition to the formation or fixation of several different mutations in mitochondrial tRNA-LeuUUR.

Base Sequence↗
PubMed1995

The effect of changes in nucleotide sequence coding for the N-terminus on expression levels of ovine growth hormone variants in Escherichia coli.

The expression levels of coding sequences for pituitary growth hormone, introduced into Escherichia coli by genetic manipulation techniques, vary markedly according to the precise sequence introduced. In order to understand the basis of this variation more fully, we have studied the relationship between the level of expression in E. coli of a series of ovine growth hormone variants and the nucleotide sequences coding for their N-terminal regions. Sequence variation resulted from the introduction of deletions, or site-directed mutations, into a plasmid containing the coding sequence for ovine growth hormone preceded by the initiation codon and 25 bases derived from beta-galactosidase or linker regions of plasmid pUC8. The expression levels of the variants varied from less than 0.01% to over 34% of the total cell protein, indicating that changes in the nucleotide sequence close to the initiation codon had a marked effect on expression level. The results of a comparison of closely related sequences in pairs of plasmids giving poor or good expression are consistent with the hypothesis that poor translation of growth hormone mRNAs is caused by the presence of secondary structures close to the initiation codon. Secondary structures are identified that appear to explain the variation in expression levels.

Animals↗
PubMed2002

Novel alternative splice variants of rat phosphodiesterase 7B showing unique tissue-specific expression and phosphorylation.

cDNA species coding for novel variants of cyclic-AMP-specific phosphodiesterases (PDEs), namely the PDE7B family, were isolated from rats and characterized. Rat PDE7B1 (RNPDE7B1) was composed of 446 amino acid residues. Rat PDE7B2 (RNPDE7B2) and PDE7B3 (RNPDE7B3), which possessed unique N-terminal sequences, consisted of 359 and 459 residues respectively. Northern hybridization analysis showed that rat PDE7B transcripts were particularly abundant in the striatum and testis. PCR analyses revealed that rat PDE7B2 transcripts were restricted to the testis and that low levels of PDE7B3 transcripts were expressed in the heart, lung and skeletal muscle. In situ hybridization analysis demonstrated that rat PDE7B transcripts were expressed in striatal neurons and spermatocytes. In spermatocytes, rat PDE7B transcripts were expressed in a stage-specific manner during spermatogenesis. The K(m) values of recombinant rat PDE7B1, PDE7B2 and PDE7B3 for cAMP were 0.05, 0.07 and 0.05 microM respectively. Each rat PDE7B variant was the most sensitive to 3-isobutyl-1-methylxanthine (IC(50) 1.5-2.1 microM). Two phosphorylation sites for cAMP-dependent protein kinase (PKA) were found in rat PDE7B1 and PDE7B3, whereas rat PDE7B2 possessed one site. PKA-dependent phosphorylation was observed in C-terminal phosphorylation sites of three rat PDE7B variants, in addition to unique N-terminal regions of rat PDE7B1 and PDE7B3. Unique tissue distribution and PKA-dependent phosphorylation of PDE7B variants suggested that each variant has a specific role for cellular functions via cAMP signalling in various tissues.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

Child↗
PubMed2005

Differential mRNA stability to endogenous ribonucleases of the coding region and 3' untranslated regions of wheat (Triticum aestivum L.) manganese superoxide dismutase genes.

The sequences of the 3' untranslated region (UTR) of the manganese superoxide dismutase (MnSOD) genes in wheat (Triticum aestivum) were found to be quite variable with different predicted thermostabilities. The degradation rates of the 3' UTR variants and the coding region were measured following exposure to endogenous nucleases. The degradation rates of the 3' UTR variants for 15 min were not significantly different, meaning the degradation rates of the 3' UTR variants were not directly related to the thermostabilities. However, the degradation rate of the coding region was significantly faster than those of the 3' UTR variants. Further investigation revealed the coding region seemed to have specific sites for degradation, indicating a possibility of increasing MnSOD expression by the degradation site alteration.

3' Untranslated Regions↗
PubMed1982

Characterization of the DNA duplication-transposition that controls the expression of two genes for variant surface glycoproteins in Trypanosoma brucei.

The genome of Trypanosoma brucei carries over a hundred genes coding for different variants of the major surface glycoprotein. Activation of some of these genes is accompanied by a duplication and transposition of the gene (the basic copy) to another region in the genome where it is transcribed. We present here physical maps of the basic and transposition-activated genes for two surface glycoproteins of Trypanosoma brucei, stock 427. In both cases the transposed segment starts 1-2 kb in front of the coding region and ends within the 3'-terminal region of the gene. The DNA segments flanking both transposed genes are indistinguishable and share a 6-kb stretch upstream and a 8-kb stretch downstream of the transposed segment not cut by several restriction endonucleases. The 5' borders of the two transposed segments are homologous and contain sequences present in many copies in the genome. A different repeated sequence has previously been found at the 3' edge of the transposed segment. The replicative transposition may, therefore, involve a unidirectional gene conversion initiated by base pairing between the edges of the transposed sequence and a single expression site elsewhere in the genome.

Animals↗