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PubMed2001

Linkage studies suggest a possible locus for developmental dyslexia on chromosome 1p.

Eight extended dyslexic families with at least four affected individuals were genotyped with twelve genetic markers spanning the Rh (rhesus factor) locus. Eleven of these markers were located on the short arm and the other was on the long arm of chromosome 1. Five theoretically derived phenotypes were used in the linkage analyses: 1) phonemic awareness; 2) phonological decoding; 3) rapid automatized naming; 4) single word reading; and 5) vocabulary. In addition, a lifetime diagnosis of dyslexia was used as a phenotype. Both parametric and non-parametric genetic analyses were completed. The results supported the importance of a putative locus on 1p. In addition, two-locus analyses assuming the interaction between a 1p locus and a 6p locus, previously shown to be of interest for dyslexia, were conducted. As a result, the nonparametric linkage (NPL) scores for rapid automatized naming and phonological decoding were significantly increased. In particular, the NPL scores for rapid automatized naming exceeded 5.0 for certain markers. These results provide strong evidence for separate but jointly acting contributions of the 1p and 6p loci to the reading impairments associated with rapid naming and suggestive evidence for a similar mechanism involving phonological decoding.

Adolescent↗
PubMed2000

The bulged nucleotide in the Escherichia coli minimal selenocysteine insertion sequence participates in interaction with SelB: a genetic approach.

The UGA codon, which usually acts as a stop codon, can also direct the incorporation into a protein of the amino acid selenocysteine. This UGA decoding process requires a cis-acting mRNA element called the selenocysteine insertion sequence (SECIS), which can form a stem-loop structure. In Escherichia coli, selenocysteine incorporation requires only the 17-nucleotide-long upper stem-loop structure of the fdhF SECIS. This structure carries a bulged nucleotide U at position 17. Here we asked whether the single bulged nucleotide located in the upper stem-loop structure of the E. coli fdhF SECIS is involved in the in vivo interaction with SelB. We used a genetic approach, generating and characterizing selB mutations that suppress mutations of the bulged nucleotide in the SECIS. All the selB suppressor mutations isolated were clustered in a region corresponding to 28 amino acids in the SelB C-terminal subdomain 4b. These selB suppressor mutations were also found to suppress mutations in either the loop or the upper stem of the E. coli SECIS. Thus, the E. coli SECIS upper stem-loop structure can be considered a "single suppressible unit," suggesting that there is some flexibility to the nature of the interaction between this element and SelB.

Bacterial Proteins↗
PubMed2000

Modulation of RNA function by aminoglycoside antibiotics.

One of the most important families of antibiotics are the aminoglycosides, including drugs such as neomycin B, paromomycin, gentamicin and streptomycin. With the discovery of the catalytic potential of RNA, these antibiotics became very popular due to their RNA-binding capacity. They serve for the analysis of RNA function as well as for the study of RNA as a potential therapeutic target. Improvements in RNA structure determination recently provided first insights into the decoding site of the ribosome at high resolution and how aminoglycosides might induce misreading of the genetic code. In addition to inhibiting prokaryotic translation, aminoglycosides inhibit several catalytic RNAs such as self-splicing group I introns, RNase P and small ribozymes in vitro. Furthermore, these antibiotics interfere with human immunodeficiency virus (HIV) replication by disrupting essential RNA-protein contacts. Most exciting is the potential of many RNA-binding antibiotics to stimulate RNA activities, conceiving small-molecule partners for the hypothesis of an ancient RNA world. SELEX (systematic evolution of ligands by exponential enrichment) has been used in this evolutionary game leading to small synthetic RNAs, whose NMR structures gave valuable information on how aminoglycosides interact with RNA, which could possibly be used in applied science.

Aminoglycosides↗
PubMedDate not supplied

[Hereditary factors in strabismus].

This retrospective study took place in the Ophthalmology Department of Douala General Hospital. The aim was to determine the importance of hereditary factors in a group of strabismic Cameroonians. In a series of 275 patients with strabismus, we found 79 familial cases (28.72%). Among them, 22.78% had more than one relative with squint and 75% had the same type of strabismus as their relative. There was no significant difference in the percentage of familial cases with regard to the type of strabismus, the sex, the mode of fixation and the impairment of ductions. As far as ametropias are concerned, only myopia showed a hereditary tendency in our series. The authors agree with the literature in that there is a significant hereditary component in the cause of strabismus, but its genetic sites are yet to be identified. There is strong hope in this direction with the decoding of the human genom and the advances in molecular biology. However, the study of familial cases is important since it allows high risk groups to be defined and screened. It thus makes it possible to successfully fight amblyopia through early detection and treatment.

Adult↗
PubMed1996

Codon reassignment in Candida species: an evolutionary conundrum.

A number of Candida species translate the standard leucine CUG codon as serine rather than as leucine. Such codon reassignment in nuclear-encoded mRNAs is unusual and raises a number of important questions about the origin of the genetic code and its continuing evolution. In particular we must establish how a codon can come to be reassigned without extinction of the species and what, if any, selective pressure drives such potentially catastrophic changes. Recent studies on the structure and identity of the novel CUG-decoding tRNA(Ser) from several different Candida species have begun to shed light on possible evolutionary mechanisms which could have facilitated such changes to the genetic code. These findings are reviewed here and a possible molecular mechanism proposed for how the standard leucine CUG codon could have become reassigned as a serine codon.

Base Sequence↗
PubMed2001

Pharmacogenetics: the Dx perspective.

The promise of the rapidly developing field of pharmacogenetics is that genetically determined propensities of individual patients to respond favorably or adversely to a given pharmacologic agent will be able to be determined prior to administration of that drug. The realization of that promise, however, is predicated on a number of developments in the capabilities of diagnostic laboratories. These developments include the introduction of automated technologies for efficiently and accurately detecting, quantifying and decoding specific nucleic acid sequences and the concomitant availability of information technology-based applications for rapidly analyzing, interpreting and then communicating complex genetic data to healthcare providers. This article will review currently available and developmental molecular diagnostic technology and in addition, describe the current status and speculate on the future of pharmacogenetic testing in the clinical laboratory.

Humans↗
PubMed1993

New insights into mRNA decoding--implications for heterologous protein synthesis.

The primary structure of a polypeptide can be predicted by translating its mRNA sequence according to the 'universal' genetic code. Yet, recent evidence has shown that a number of nonstandard translational events may occur in cells, generating microheterogeneity in the translation product at the amino acid level. Such events can be programmed by sequences within the mRNA, or may just represent nonprogrammed errors that occur during translation as a result of depletion of specific aminoacyl-tRNAs. The potential occurrence of such errors must be considered and steps taken both to identify and eliminate them when expression strategies are being developed for producing recombinant proteins for human therapeutic use.

Codon↗
PubMed2001

Etiology of reading difficulties and rapid naming: the Colorado Twin Study of Reading Disability.

Children with reading deficits perform more slowly than normally-achieving readers on speed of processing measures, such as rapid naming (RN). Although rapid naming is a well-established correlate of reading performance and both are heritable, few studies have attempted to assess the cause of their covariation. Measures of rapid naming (numbers, colors, objects, and letters subtests), phonological decoding, orthographic choice, and a composite variable (DISCR) derived from the reading recognition, reading comprehension, and spelling subtests of the Peabody Individual Achievement Test were obtained from a total of 550 twin pairs with a positive school history of reading problems. Basic DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data confirmed the heritable nature of phonological decoding, orthographic choice, DISCR, and rapid-naming composites. Bivariate DF models were employed to examine the extent to which deficits in the three reading-related measures covary genetically with rapid naming. Significant bivariate heritability estimates for each of the reading measures with the numbers and letters rapid-naming composite were also obtained. As expected, univariate sib-pair linkage analyses indicated the presence of a quantitative trait locus (QTL) on chromosome 6p21.3 for phonological decoding and orthographic choice deficits. Bivariate linkage analyses were then conducted to test the hypothesis that this QTL for reading difficulties is pleiotropic for slower performance on RN tasks. The results obtained from these analyses did not provide substantial evidence that the 6p QTL for reading difficulties has significant effects on rapid naming; however, larger samples would be required to test this hypothesis more rigorously.

Adolescent↗
PubMed1996

Functional specificity of amino acid at position 246 in the tRNA mimicry domain of bacterial release factor 2.

The termination of protein synthesis in bacteria requires codon-specific polypeptide release factors RF-1 (UAG/UAA specific) and RF-2 (UGA/UAA specific). We have proposed that release factors mimic tRNA and recognize the stop codon for polypeptide release (Nakamura et al (1996) Cell 87, 147-150). In contrast to the textbook view, genetic experiments have indicated that Escherichia coli RF-2 terminates translation very weakly at UAA while Salmonella RF-2 decodes this signal efficiently. Moreover, an excess of E coli RF-2 was toxic to cells while an excess of Salmonella RF-2 was not. These two RF-2 proteins are identical except for 16 out of 365 amino acids. Fragment swap experiments and site-directed mutagenesis revealed that a residue at position 246 is solely responsible for these two phenotypes. Upon substituting Ala (equivalent to Salmonella RF-2) for Thr-246 of E coli RF-2, the protein acquired increased release activity for UAA as well as for UGA. These results led us to conclude that E coli RF-2 activity is potentially weak and that the amino acid at position 246 plays a crucial role, not for codon discrimination, but for stop codon recognition or polypeptide release, presumably constituting an essential moiety of tRNA mimicry or interacting with peptidyltransferase centers of the ribosome.

Amino Acid Sequence↗
PubMed2000

Familial aggregation of dyslexia phenotypes.

There is evidence for genetic contributions to reading disability, but the phenotypic heterogeneity associated with the clinical diagnosis may make identification of the underlying genetic basis difficult. In order to elucidate distinct phenotypic features that may be contributing to the genotypic heterogeneity, we assessed the familial aggregation patterns of Verbal IQ and 24 phenotypic measures associated with dyslexia in 102 nuclear families ascertained through probands in grades 1 through 6 who met the criteria for this disorder. Correlations between relatives were computed for all diagnostic phenotypes, using a generalized estimating equation (GEE) approach. GEE is a recently developed semiparametric method for handling correlated data. The method is robust to model misspecification and flexible in adjusting for the subjects' characteristics and pedigree sizes as well as for the ascertainment process, while estimating the correlations between related subjects. The Nonword Memory (NWM) subtest of a prepublication version of the Comprehensive Test of Phonological Processing (CTOPP) and Phonemic Decoding Efficiency (PDE) subtest of a prepublication version of the Test of Word Reading Efficiency (TOWRE) showed correlation patterns in relatives that are strongly supportive of a genetic basis. The Wechsler Scale Digit Span, the Word Attack subtest of the Woodcock Reading Mastery Test--Revised, and the Spelling subtest of the Wide Range Achievement Test--Third Edition had slightly weaker evidence of a genetic basis. Five additional phenotypes (the Spelling subtest of the Wechsler Individual Achievement Test, the Accuracy, Rate, and Comprehension subtests of the Gray Oral Reading Test--Third Edition, and Rapid Automatized Naming of Letters and Numbers) gave suggestive evidence of such a pattern. The results cross-validate in that evidence for a pattern consistent with a genetic basis was obtained for two measures of phonological short-term memory (CTOPP Nonword Memory and WISCIII or WAIS-R Digit Span), for two measures of phonological decoding (WRMT-R Word Attack and TOWRE Phonemic Decoding Efficiency), and for two measures of spelling from dictation (WRAT-3 Spelling and, to a lesser extent, WIAT Spelling). These measures are thus good candidates for more sophisticated segregation analyses that can formulate models for incorporation into linkage analyses.

Adult↗
PubMed2026

The Potential Link Between Eosinophilic Esophagitis and Food Allergy: Inflammatory Pathogenesis and Management.

Eosinophilic esophagitis (EoE) has transitioned from an isolated gastrointestinal disorder to a recognized type 2 immune-mediated allergic disease, most likely representing a late manifestation of the atopic march. This comprehensive review examines the complex inflammatory pathogenesis linking EoE and food allergy, and critically discusses the mechanisms of disease induction, dietary treatments, and emerging clinical challenges. While genome-wide association studies identify shared susceptibility loci with classic atopy, EoE exhibits distinct tissue-specific pathways, particularly dominated by the local interleukin (IL)-13 axis and highly esophagus-selective proteases like Calpain-14. This unique immunological interplay is clinically epitomized by food oral immunotherapy (OIT)-induced EoE. During OIT, systemic immune reprogramming successfully drives immune tolerance-marked by a robust increase in plasma food-specific IgG4-but fails at the local level, due to the persistence of pathogenic Th2 cells and aberrant mucosal IgG4 immune complex deposition within the esophageal lamina propria. Regarding therapeutic management, conventional skin and serum allergy testing remain highly inaccurate in identifying dietary triggers, rendering test-guided diets ineffective. Conversely, empiric elimination diets achieve robust histological remission, ranging from standardized six-food restrictions to pragmatic single-food approaches targeting cow's milk. Furthermore, novel insights into industrial milk processing (such as UHT sterilization and homogenization) and specific beta-casein genetic variants (A1 vs A2) highlight how altered protein structures generate neoantigens that accelerate esophageal immunogenicity. In conclusion, decoding the divergent immunological mechanisms operating in the refractory esophagus is essential to move beyond trial-and-error dietary interventions towards non-invasive monitoring tools, precision medicine, and optimized biological therapies in EoE management.

Calpain14↗
PubMed2003

Comparison of X-ray crystal structure of the 30S subunit-antibiotic complex with NMR structure of decoding site oligonucleotide-paromomycin complex.

Aminoglycoside antibiotics that bind to 16S ribosomal RNA in the aminoacyl-tRNA site (A site) cause misreading of the genetic code and inhibit translocation. Structures of an A site RNA oligonucleotide free in solution and bound to the aminoglycosides paromomycin or gentamicin C1a have been determined by NMR. Recently, the X-ray crystal structure of the entire 30S subunit has been determined, free and bound to paromomycin. Distinct differences were observed in the crystal structure, particularly at A1493. Here, the NMR structure of the oligonucleotide-paromomycin complex was determined with higher precision and is compared with the X-ray crystal structure of the 30S subunit complex. The comparison shows the validity of both structures in identifying critical interactions that affect ribosome function.

Anti-Bacterial Agents↗
PubMed2003

Genetic and epigenetic alterations of 9p21 gene products in benign and malignant tumors of the head and neck.

The multistep process of tumorigenesis has not been decoded to date, although numerous investigations into probable molecular changes have meanwhile been conducted. However, not only DNA changes or loss of alleles cause deregulation of gene function, but also epigenetic alterations (e.g. methylation) result in functional loss. The INK4a-ARF (CDKN2A) locus, located on chromosome 9p21, encodes two functionally distinct tumor suppressor genes, p14ARF and p16INK4a, which play active roles in the p53 and Rb tumor suppressive pathways. We therefore examined not only p16 and p14 proteins, but also alterations of the INK4a-ARF locus, including methylation and loss of heterozygosity in benign and malignant tumors of the head and neck (squamous cell carcinomas and pleomorphic adenomas). In benign pleomorphic adenomas, methylation of p14ARF was found in 1 out of 42 (2%) cases, whereas alterations of p16INK4a occurred in 12/42 (29%) pleomorphic adenomas. In HNSCC, methylation of p16INK4a occurred in 16 out of 50 (32%) carcinomas. P14ARF was found to be methylated in 8 out of 50 cases (16%). Our results demonstrate that alterations of the INK4a-ARF locus are frequent and important events not only in the carcinogenesis of malignant, but also in benign tumors.

Adenoma, Pleomorphic↗
PubMed1988

Signals determining translational start-site recognition in eukaryotes and their role in prediction of genetic reading frames.

A special methionyl-tRNA (RNAi) is universally required to initiate translation. The conversation of this reactant throughout evolution, as well as its unusual decoding properties, suggested an alternate mechanism for tRNA-mRNA interactions at initiation. We have reported that the sequence of bases neighboring the start codons of many eubacterial genes are complementary not only to the 16S rRNA 3' end and to the anticodon of tRNAi, but, also, have the potential to base-pair the D, T or extended anticodon loops of this tRNAi. The coding properties of tRNAi and mutations that affect translation suggest that these signals may function. This hypothesis explains the observation that unusual triplets can start prokaryotic and mitochondrial genes and predicts the occurrence of other reading frames. Furthermore, it suggests a unifying model of chain initiation based on RNA-RNA contacts and displacements. Here we examine the start domain of 290 eukaryotic genes for their ability to base-pair the tRNAi loops and the 18S rRNA. We observe that both methionine start, and methionine coding regions have the potential to pair with the 18S rRNA, but that the nucleotide distribution about start codons strongly favoured such pairings over that near internal AUGs. The 5' extended anticodon of tRNAi is methylated, and was not represented in the mRNA with high frequency. However, the tetramer AUGg did occur with high frequency in the start domain. A modification of the tRNAi T loop also decreases its base-pairing potential. Interestingly, complementarity to the T loop did not occur with high frequency in the start sites. The early coding region, 10 to 34 nucleotides 3' to the initiator AUG, is complementary to the tRNAi D loop in many cases, while no such affinity is found near internal AUGs. The nucleotides around initiator AUGs were heavily biassed toward the sequence gccaccAUGgcg. No such tendency was noted around internal AUGs. Although the role of this sequence bias is unclear, the sequence gccaccAUGg has been shown by Kozak to promote initiation. Another distinguishing feature was a C-rich tract 7 to 34 nucleotides 5' to the initiator AUGs. Ability to pair with more than eight bases of the start consensus sequence, matching of 6 or 7 nucleotides to the D loop on the 3' side, an C-richness on the 5' side were used as criteria for distinguishing start AUGs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Were RNA replication and translation directly coupled in the RNA (+protein?) World?

The ribosome is proposed to have evolved from an ancestor that simultaneously replicated and translated template RNA. At its decoding site, this ancestor to the ribosome carried a ribozyme that assembled product RNA by sequentially ligating anticodon triplets excised from tRNAs. This ribozyme was the ancestor of the Group I introns, which are still present on some ribosomal RNA precursors. Coupling of reversible RNA replication by transesterification with the thermodynamically favourable process of transpeptidation provides a rationale for the evolution of the complete ribosome as a replicase for large RNAs in the RNA (+protein?) world. A detailed and experimentally verifiable mechanism can be proposed for simultaneous replication and translation. Sequence requirements for recognition of the decoding complex as a substrate helix by these ribozymes are consistent with earlier models for the origin of the genetic code, but require an indirect mode for ribosomal self-replication. This proposal has the potential to explain the location of Group I introns in the anticodon loops of some tRNAs.

Animals↗
PubMed1994

Tradescantia stamen hair mutation bioassay.

The Tradescantia stamen hair mutation (Trad-SH) assay (clone 4430) was evaluated for its efficiency and reliability as a screen for mutagens in an IPCS collaborative study on plant systems. Four coded chemicals, i.e. azidoglycerol (AG, 3-azido-1,2-propanediol), N-methyl-N-nitrosourea (MNU), sodium azide (NaN3) and maleic hydrazide (MH) were distributed by the Radian Corporation to the five laboratories in five different countries for testing mutagenicity. Pink mutations were scored between the 7th and 14th day according to a standard protocol. Test results from the five individual laboratories were analyzed and compared after decoding. One out of the two laboratories that conducted tests on AG demonstrated that AG is a mutagen with genetically effective doses ranging from 50 to 100 micrograms/ml. MH yielded positive responses in all laboratories but no linear dose-response pattern was observed. The effective dose range for MH was between 1 and 45 micrograms/ml. The mutagenicity of MNU was reported by five laboratories in the dose range between 10 and 80 micrograms/ml. NaN3, which exhibited a relatively high degree of toxicity, elicited a positive mutagenic response in three of the five laboratories in which it was tested. As with MNU the effective dose for NaN3 ranged between 3 and 80 micrograms/ml. The results from the current study substantiate the Trad-SH assay as a reliable system for screening chemicals for their potential mutagenic effects. Although the study was carried out exclusively under laboratory conditions, a survey of the current literature would indicate that the Trad-SH assay could be an effective in situ monitor of gaseous, liquid, and radioactive pollutants as well.

Azides↗