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PubMed1991

Sequences of three dsRNAs associated with La France disease of the cultivated mushroom (Agaricus bisporus).

La France disease of the cultivated mushroom, Agaricus bisporus, is known to be associated with the presence of a number of dsRNA segments. The nucleotide sequences of the dsRNAs M2 (1.3 kb), M1 (1.55 kb) and L3 (2.8 kb), invariably associated with the disease, were determined. Putative coding sequences for proteins with molecular weights of 38, 40 and 87 kDa were found for M2, M1 and L3 dsRNAs, respectively. The average G + C content of these dsRNAs was 43%, close to that of A. bisporus nuclear DNA. The nucleotide sequences, as well as the amino acid sequences, appear to be unique, as no matching sequences could be found among databases. S3 dsRNA (0.39 kb), which is occasionally found in large amounts in diseased mushrooms, is an internally deleted variant of M2 dsRNA and is largely composed of the non-coding ends of that dsRNA.

Agaricus↗
PubMed2003

The substrate specificity-determining amino acid code of 4-coumarate:CoA ligase.

To reveal the structural principles determining substrate specificity of 4-coumarate:CoA ligase (4CL), the crystal structure of the phenylalanine activation domain of gramicidin S synthetase was used as a template for homology modeling. According to our model, 12 amino acid residues lining the Arabidopsis 4CL isoform 2 (At4CL2) substrate binding pocket (SBP) function as a signature motif generally determining 4CL substrate specificity. We used this substrate specificity code to create At4CL2 gain-of-function mutants. By increasing the space within the SBP we generated ferulic- and sinapic acid-activating At4CL2 variants. Increasing the hydrophobicity of the SBP resulted in At4CL2 variants with strongly enhanced conversion of cinnamic acid. These enzyme variants are suitable tools for investigating and influencing metabolic channeling mediated by 4CL. Knowledge of the 4CL specificity code will facilitate the prediction of substrate preference of numerous, still uncharacterized 4CL-like proteins.

Amino Acid Motifs↗
PubMed2006

Common genetic polymorphisms affect the human requirement for the nutrient choline.

Humans eating diets deficient in the essential nutrient choline can develop organ dysfunction. We hypothesized that common single nucleotide polymorphisms (SNPs) in genes involved in choline metabolism influence the dietary requirement of this nutrient. Fifty-seven humans were fed a low choline diet until they developed organ dysfunction or for up to 42 days. We tested DNA SNPs for allelic association with susceptibility to developing organ dysfunction associated with choline deficiency. We identified an SNP in the promoter region of the phosphatidylethanolamine N-methyltransferase gene (PEMT; -744 G-->C; rs12325817) for which 18 of 23 carriers of the C allele (78%) developed organ dysfunction when fed a low choline diet (odds ratio 25, P=0.002). The first of two SNPs in the coding region of the choline dehydrogenase gene (CHDH; +318 A-->C; rs9001) had a protective effect on susceptibility to choline deficiency, while a second CHDH variant (+432 G-->T; rs12676) was associated with increased susceptibility to choline deficiency. A SNP in the PEMT coding region (+5465 G-->A; rs7946) and a betaine:homocysteine methyltransferase (BHMT) SNP (+742 G-->A; rs3733890) were not associated with susceptibility to choline deficiency. Identification of common polymorphisms that affect dietary requirements for choline could enable us to identify individuals for whom we need to assure adequate dietary choline intake.

Choline↗
PubMed1994

The Epstein-Barr virus EBNA-2 gene in oral hairy leukoplakia: strain variation, genetic recombination, and transcriptional expression.

Oral hairy leukoplakia (HLP) lesions frequently contain defective Epstein-Barr virus (EBV) genomes with deletions in the EBNA-2 gene that abundantly replicate and persist within the lesion. To characterize these viral strains and recombinant variants, the EBNA-2 gene in EBV DNA from several different HLP biopsy specimens was analyzed. Amplification of EBNA-2 coding sequences by PCR demonstrated the presence in HLP of intact EBNA-2 genes as well as a variety of internally deleted variants of both EBNA-2A and EBNA-2B. Some of the deletion variants evolved within the HLP lesion from intact EBNA-2 genes, while other variants appeared to be transmissible strains that directly infected the lesion. Intrastrain recombination within the HLP lesion also generated variation within the EBNA-2 polyproline region. Cloning and sequencing of HLP cDNA demonstrated transcription from the internally deleted EBNA-2 open reading frame, indicating that these variant genes are expressed in HLP. Comparative analysis of the HLP EBNA-2 sequences confirmed previous findings of EBV coinfection with multiple types and strains. Sequence variation of these wild-type genes demonstrated that EBNA-2A sequences distinguish at least two separate strains and a variety of substrains of EBV type 1. Two of the HLP EBNA-2A sequences contained amino acid changes in a cytotoxic T-cell epitope within an otherwise highly conserved region of the gene. These data indicate that EBV coinfection, strain variation, and recombination within the EBNA-2 gene are common features of HLP and suggest that the expression of internally deleted EBNA-2 variants could contribute to EBV pathogenesis in permissive infection.

Amino Acid Sequence↗
PubMed1987

Molecular principles of antigenic variation in Neisseria gonorrhoeae.

The genome of Neisseria gonorrhoeae harbours many gene loci for the production of variant pili. Strain MS11 has two expression genes (pilE) with promoter and complete coding sequences. The remaining genes are silent (pilS) lacking the promoter and the conservative amino terminals coding sequences of pilin. The pilus genes consist of six variable minicassettes (mc's), that are flancked by strictly conserved sequences. Upon phase (P+ to P+) and antigenic (P+ to P-, or vice versa) transitions minicassettes from silent loci are transferred from silent pilus gene copies to the expression gene by gene conversion. P- variants resulting from such rearrangements still produce pilin mRNA as well as pilin, but only a few are found on the surface of those gonococci.

Antigenic Variation↗
PubMed1993

BK virus antigenic variants: sequence analysis within the capsid VP1 epitope.

DNA sequences for the VP1 gene which codes for the major capsid protein of BK virus (BKV) and may be responsible for antigenic variability were determined for seven BKV isolates. The observed sequence differences and those previously reported correlate with the typing of isolates into four groups by haemagglutination inhibition. Amino acid coding alterations were found to be clustered within residues 61 to 83. Each antigenic group was found to have a characteristic amino acid sequence between residues 61 and 83. Several clones originating from a single isolate, although differing slightly in restriction enzyme digestion patterns, were found to be identical in this region. The VP1 sequences of three of the four groups were analysed by hydropathy plots and two hydrophilic areas of high antigenicity were identified. One of these corresponds to residues 61 to 83 and it is postulated that this region is the epitope responsible for serotypic differences between BK isolates.

Amino Acid Sequence↗
PubMed1995

Failure to detect Glut4-Ile383 and IR-Gln1152 variants in NIDDM (non-insulin dependent diabetes mellitus) and control subjects in an Italian population.

Insulin receptor (IR) and insulin-responsive glucose transporter (Glut4) represent two candidate genes involved in the development of non-insulin dependent diabetes mellitus (NIDDM); detection of molecular alterations in these genes might explain their possible contribution to NIDDM. Recently, mutations within the coding region of IR and Glut4 have identified: they include the Glut4Ile383 and IRGln1152 variants which were found at low frequencies in diabetic Caucasian populations. In this study Italian NIDDM patients and control subjects were analysed and mutated alleles were not found. Therefore in our population these variants appear to have little relevance to the genetic susceptibility to NIDDM.

Base Sequence↗
PubMed2005

Detection of a single nucleotide polymorphism in the human alpha-lactalbumin gene: implications for human milk proteins.

Variability in the protein composition of breast milk has been observed in many women and is believed to be due to natural variation of the human population. Single nucleotide polymorphisms (SNPs) are present throughout the entire human genome, but the impact of this variation on human milk composition and biological activity and infant nutrition and health is unclear. The goals of this study were to characterize a variant of human alpha-lactalbumin observed in milk from a Filipino population by determining the location of the polymorphism in the amino acid and genomic sequences of alpha-lactalbumin. Milk and blood samples were collected from 20 Filipino women, and milk samples were collected from an additional 450 women from nine different countries. alpha-Lactalbumin concentration was measured by high-performance liquid chromatography (HPLC), and milk samples containing the variant form of the protein were identified with both HPLC and mass spectrometry (MS). The molecular weight of the variant form was measured by MS, and the location of the polymorphism was narrowed down by protein reduction, alkylation and trypsin digestion. Genomic DNA was isolated from whole blood, and the polymorphism location and subject genotype were determined by amplifying the entire coding sequence of human alpha-lactalbumin by PCR, followed by DNA sequencing. A variant form of alpha-lactalbumin was observed in HPLC chromatograms, and the difference in molecular weight was determined by MS (wild type=14,070 Da, variant=14,056 Da). Protein reduction and digestion narrowed the polymorphism between the 33rd and 77th amino acid of the protein. The genetic polymorphism was identified as adenine to guanine, which translates to a substitution from isoleucine to valine at amino acid 46. The frequency of variation was higher in milk from China, Japan and Philippines, which suggests that this polymorphism is most prevalent in Asia. There are SNPs in the genome for human milk proteins and their implications for protein bioactivity and infant nutrition need to be considered.

Amino Acid Sequence↗
PubMed1996

The E6 variant proteins E6I-E6IV of human papillomavirus 16: expression in cell free systems and bacteria and study of their interaction with p53.

Several species of alternatively spliced mRNAs are transcribed from the E6 gene region of human papillomavirus (HPV) 16. These have the coding capacity for either the full length E6 of 151 amino acids (aa) or four truncated variants, E6I-E6IV, of 43-64 aa. As the first step to identify the putative E6 variants and their functions, we generated cDNAs corresponding to the various E6 open reading frames (ORF) and examined their expression employing in vitro transcription/translation systems and the bacterial pET system. In wheat germ extract, in vitro translation resulted in the production of all five proteins, E6 and E6I-E6IV. These proteins were also expressed as stable fusion proteins from the pET16b and pET17 x b vectors in Escherichia coli. Mobilites of the E6 variant proteins on SDS-acrylamide gels were consistent with their predicted sizes. The authenticity of the synthesized proteins was confirmed by immunoprecipitation with specific antibodies directed against epitopes in the N-terminal portion of E6 as well as antibodies raised against the individual variant proteins produced in E. coli. In rabbit reticulocyte lysate, however, only the full length E6 and the E6IV variant were synthesized. This could be due to inefficient translation as well as lower stability of the short variants. E6I-III, in reticulocyte lysate (RTL). The ability of the E6 variants to associate with p53 and target its proteolytic degradation in vitro, was examined in coimmunoprecipitation assays, using in vitro synthesized proteins and monoclonal antibodies to p53. Results of these assays indicated that only the full length E6 efficiently binds to and promotes the degradation of p53. The E6 variants E6I-E6IV, although able to associate with p53 at a low efficiency, were unable to target its degradation.

Amino Acid Sequence↗
PubMed2005

CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome.

Rett syndrome (RTT) is a severe neurodevelopmental disorder almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Most patients affected by classic RTT and a smaller percentage of patients with the milder form 'preserved speech variant' have either point mutations or deletions/duplications in the MECP2 gene. Recently, mutations in the CDKL5 gene, coding for a putative kinase, have been found in female patients with a phenotype overlapping with that of RTT. Here, we report two patients with the early seizure variant of RTT, bearing two novel CDKL5 truncating mutations, strengthening the correlation between CDKL5 and RTT. Considering the similar phenotypes caused by mutations in MECP2 and CDKL5, it has been suggested that the two genes play a role in common pathogenic processes. We show here that CDKL5 is a nuclear protein whose expression in the nervous system overlaps with that of MeCP2, during neural maturation and synaptogenesis. Importantly, we demonstrate that MeCP2 and CDKL5 interact both in vivo and in vitro and that CDKL5 is indeed a kinase, which is able to phosphorylate itself and to mediate MeCP2 phosphorylation, suggesting that they belong to the same molecular pathway. Furthermore, this paper contributes to the clarification of the phenotype associated with CDKL5 mutations and indicates that CDKL5 should be analyzed in each patient showing a clinical course similar to RTT but characterized by a lack of an early normal period due to the presence of seizures.

Age of Onset↗
PubMed2024

Novel pathogenic variant in a mild case of type B molybdenum cofactor deficiency: case report and literature review.

BACKGROUND: Molybdenum cofactor deficiency (MoCD) is a rare metabolic disorder caused by pathogenic variants in the highly conserved biosynthetic pathway of molybdenum cofactor (MoCo), resulting in sulfite intoxication. MoCD may present in a clinically severe, fatal form marked by intractable seizures after birth, hyperekplexia, microcephaly and cerebral atrophy, or a later onset form with a more varied clinical course. Three types of MoCD have been described based on the effected gene along the MoCo synthesis pathway: type A (MOCS1); type B (MOCS2 or MOCS3) and type C (GPHN). The MOCS2 gene is bicistronic, encoding the small (MOCS2A) and large (MOCS2B) subunits with an overlapping coding region. This case report describes a patient with the first known variant causative of mild disease in the overlapping bicistronic region (c.263 G > C) and the first ever described in the highly conserved C-terminal glycine-glycine motif of MOCS2A. CASE PRESENTATION: The patient developed normally until age 12 months when she presented in the setting of acute illness with developmental regression, low serum uric acid, and MRI with bilateral globus pallidus (GP) injury. Exome sequencing identified a homozygous variant of unknown significance in the MOCS2 gene and the diagnosis of MoCD type B was confirmed by the patient's low serum uric acid coupled with elevated urine sulfocysteine and associated metabolites, resulting in gene reclassification. Nearly four years after her initial presentation she has demonstrated progress in language and motor domains, consistent with a mild phenotype of MoCD. CONCLUSIONS: The case emphasizes challenges in identifying atypical forms of rare diseases, the importance of exome sequencing to identify mild cases of MoCD, and the ongoing challenges with understanding the MOCS2 gene. While one FDA approved treatment exists for MoCD type A, further research into the mechanisms of phenotype-genotype differences among this patient population may aid in additional therapeutic options for MoCD.

Female↗
PubMed2024

SpRY-mediated screens facilitate functional dissection of non-coding sequences at single-base resolution.

CRISPR mutagenesis screens conducted with SpCas9 and other nucleases have identified certain cis-regulatory elements and genetic variants but at a limited resolution due to the absence of protospacer adjacent motif (PAM) sequences. Here, leveraging the broad targeting scope of the near-PAMless SpRY variant, we have demonstrated that saturated SpRY mutagenesis and base editing screens can faithfully identify functional regulatory elements and essential genetic variants for target gene expression at single-base resolution. We further extended this methodology to investigate a genome-wide association study (GWAS) locus at 10q22.1 associated with a red blood cell trait, where we identified potential enhancers regulating HK1 gene expression, despite not all of these enhancers exhibiting typical chromatin signatures. More importantly, our saturated base editing screens pinpoint multiple causal variants within this locus that would otherwise be missed by Bayesian statistical fine-mapping. Our approach is generally applicable to functional interrogation of all non-coding genomic elements while complementing other high-coverage CRISPR screens.

Humans↗
PubMed1985

Measurement of gene number for seed storage proteins in Pisum.

We have measured the numbers of genes coding for the three seed storage proteins, vicilin, convicilin and legumin, in a number of Pisum genotypes of variant protein composition. No difference in gene number existed among P. sativum genotypes for any of the proteins. There were differences in the number of genes coding for individual proteins with approximately 11 genes (per haploid genome) for vicilin, 8 genes for legumin and 1 gene for convicilin.

DNA Restriction Enzymes↗
PubMed1998

Integration of the analytical and alphabetical ICD10 in a coding help system. Proposal of a theoretical model for the ICD representation.

UNLABELLED: In French hospitals, medical diagnosis coding with the ICD10 is commonly performed and the use of effective tools would help coders in their task. AIM OF THIS WORK: To ameliorate an existing coding help system. This system, which already consists of the ICD10 analytical index, would be increased with the terms of the alphabetical index that includes lexical variants and additional terms as well. The addition of the second volume of the ICD would allow the coding of more terms and would lessen documentary silence. METHODS: The first step of this work was a careful study of a theoretical model of the ICD content. Then the alphabetical index file was submitted to a lexical analysis, and it was automatically transformed to be integrated into the existing coding help system. RESULTS: Compromise had to be made between a theoretical model and between what could be obtained in practice by an automatic processing of the file. Finally the alphabetical index was added to the initial thesaurus, which represents 42,000 terms and 4,000 additional words. Links between words and codes were also considerably increased, which has enhanced the searching possibilities of the tool and lessen documentary silence. Conversely the research time has been increased. CONCLUSION: Difficulties have to be encountered when trying to turn a manual tool into an automatic research tool.

Abstracting and Indexing↗
PubMed2004

A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency.

Congenital intrinsic factor (IF) deficiency is a disorder characterized by megaloblastic anemia due to the absence of gastric IF (GIF, GenBank NM_005142) and GIF antibodies, with probable autosomal recessive inheritance. Most of the reported patients are isolated cases without genetic studies of the parents or siblings. Complete exonic sequences were determined from the PCR products generated from genomic DNA of five affected individuals. All probands had the identical variant (g.68A>G) in the second position of the fifth codon in the coding sequence of the gene that introduces a restriction enzyme site for Msp I and predicts a change in the mature protein from glutamine(5) (CAG) to arginine(5) (CGG). Three subjects were homozygous for this base exchange and two subjects were heterozygous, one of which was apparently a compound heterozygote at positions 1 and 2 of the fifth codon ([g.67C>G] + [g.68A>G]). The other patient, heterozygous for position 2, had one heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at base pair g.68 (A>G) and expressed in COS-7 cells. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native IF. The allelic frequency of g.68A>G was 0.067 and 0.038 in two control populations. This sequence aberration is not the cause of the phenotype, but is associated with the genotype of congenital IF deficiency and could serve as a marker for inheritance of this disorder.

Adult↗
PubMed2024

Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation.

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.

Humans↗
PubMed2026

Genome-wide detection of human 5' UTR variants that impact protein translation.

The 5' untranslated region (5' UTR) of messenger RNAs (mRNAs) plays a central role in regulating protein synthesis initiation, particularly through the Kozak sequence and upstream open reading frames (uORFs). Genetic variants within these regulatory elements could affect translation, altering gene expression and contributing to clinical phenotypes in humans. We developed a computational method called 5ULTRA (5' Untranslated Region Annotation) for analysis of whole-exome sequencing and whole-genome sequencing data to detect, annotate, and prioritize 5' UTR variants with potential translation impact. 5ULTRA identifies single-nucleotide variants, indels, and splicing variants that affect uORFs by creating or disrupting start/stop codons and that alter Kozak sequence strength of either the uORFs or the main coding sequence. 5ULTRA incorporates recent uORF databases and provides comprehensive annotations. 5ULTRA implements a machine-learning score to prioritize candidate variants with predicted effects on translation and also provides specific mechanistic predictions. The score correlates strongly with experimentally measured protein-level effects of 5' UTR variants. We applied 5ULTRA to multiple genetics datasets across diverse disease contexts, identifying candidate variants including potential cancer-driving somatic mutations predicted to decrease ABI1 level or increase NRAS abundance; common variants associated with traits such as multiple sclerosis, lung function, and cardiovascular function, by altering protein levels of TAGAP, VRTN, and SPAAR, respectively; and rare germline variants in our cohort, including a splicing variant of RPSA leading to 5' UTR sequence alteration that causes congenital asplenia and a variant of TNF that could predispose to tuberculosis.

Humans↗
PubMed1998

Identification and characterization of variant alleles of human acetyltransferase NAT1 with defective function using p-aminosalicylate as an in-vivo and in-vitro probe.

Although several variant alleles at the human NAT1 gene locus have been reported, their relationship to phenotypic variations in NAT1 function remains unclear. We have used in-vivo and invitro phenotyping tests, along with PCR-based cloning and heterologous expression, to investigate the extent of variation in NAT1 function and to characterize novel allelic variants at the NAT1 gene locus. The NAT1-selective substrate p-aminosalicylic acid (PAS) was used as a probe for NAT1 function. In-vivo PAS acetylation rates were estimated by determining the ratio of PAS to N-acetylated PAS (AcPAS) in urine and plasma following the oral ingestion of Nemasol Sodium. Excluding outliers, a 65-fold variation in the urinary AcPAS:PAS ratio was observed (n = 144), while a 5.6-fold variation in the plasma AcPAS:PAS ratio was seen in a subset (n = 19) of this sample. Urinary and plasma ratios correlated moderately (r = 0.74, p < 0.0005). One individual (case 244) had a marked impairment of PAS N-acetylation, with 10-fold lower urinary and plasma AcPAS:PAS ratios compared with other subjects. Biochemical investigations in whole blood lysates from case 244 suggested a NAT1 kinetic defect, with a 20-fold increased apparent K(m) for PAS and a 90-fold decreased Vmax for AcPAS formation. We subcloned, sequenced and expressed the protein-coding regions of the NAT1 alleles from case 244 and from seven other selected probands. Sequence analysis revealed the presence of two new variant alleles, designated as NAT1 x 14 and NAT1 x 15, in case 244, as well as one variant, NAT1 x 11, which has been observed in previous investigations. NAT1 x 14 contained a missense mutation (G560-->A) that is predicted to change a single amino acid (Arg187-->Gln), as well as two 3' non-coding region mutations (T1088-->A and C1095-->A) that have previously been observed in the NAT1 x 10 allelic variant. NAT1 x 15 had a single nonsense mutation (C559-->T; Arg187-->stop) and, thus, encodes a truncated protein. The activity of recombinant NAT1 14 mirrored the defective enzyme function in whole blood lysates from case 244, while NAT1 15 was completely inactive. Expressed NAT1 11, on the other hand, had identical activity to the wild type NAT1 4 allele, suggesting that the coding region mutations in this variant are functionally silent. The frequencies of NAT1 x 11, NAT1 x 14 and NAT1 x 15 were 0.021, 0.028 and 0.014 (n = 288 alleles), respectively, suggesting that they are relatively rare in our predominantly Caucasian sample.

Adolescent↗