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PubMed1998

Connexin-26 mutations in sporadic and inherited sensorineural deafness.

BACKGROUND: Hearing impairment affects one infant in 1000 and 4% of people aged younger than 45 years. Congenital deafness is inherited or apparently sporadic. We have shown previously that DFNB1 on chromosome 13 is a major locus for recessive deafness in about 80% of Mediterranean families and that the connexin-26 gene gap junction protein beta2 (GJB2) is mutated in DFNB1 families. We investigated mutations in the GJB2 gene in familial and sporadic cases of deafness. METHODS: We obtained DNA samples from 82 families from Italy and Spain with recessive non-syndromic deafness and from 54 unrelated participants with apparently sporadic congenital deafness. We analysed the coding region of the GJB2 gene for mutations. We also tested 280 unrelated people from the general populations of Italy and Spain for the frameshift mutation 35delG. FINDINGS: 49% of participants with recessive deafness and 37% of sporadic cases had mutations in the GJB2 gene. The 35delG mutation accounted for 85% of GJB2 mutations, six other mutations accounted for 6% of alleles, and no changes in the coding region of GJB2 were detected in 9% of DFNB1 alleles. The carrier frequency of mutation 35delG among people from the general population was one in 31 (95% CI one in 19 to one in 87). INTERPRETATION: Mutations in the GJB2 gene are a major cause of inherited and apparently sporadic congenital deafness. Mutation 35delG is the most common mutation for sensorineural deafness. Identification of 35delG and other mutations in the GJB2 gene should facilitate diagnosis and counselling for the most common genetic form of deafness.

Chromosomes, Human, Pair 13↗
PubMed2001

Interpersonal control and expressed emotion in families of persons with schizophrenia: change over time.

This study examined communication patterns in 62 families of persons with schizophrenia, comparing families with relatives who were low expressed emotion (EE) at the beginning and end of a 2-year study, those who were high EE at the beginning and end, and those whose EE status changed. Interaction was coded with the Relational Control Coding System and analyzed as a Markov process. Dialogues in the stable low-EE and stable high-EE families were rather similar initially, and both groups showed increasing flexibility at year 1. However, at year 2, low-EE dyads showed increasingly complex structure and flexibility in control, but high-EE dyads showed simpler structure and rigidly controlling patterns. When EE status changed, so did the structure of the dialogues and the patterning of control. Although earlier research found more "tightly joined" systems in families of high-EE relatives, it may be that over time, these family members distance from each other and so are less connected. It is also possible that relatives who remain high EE despite intervention are a subset of high-EE relatives who need more support or different therapeutic approaches to maintain change.

Adult↗
PubMed2001

Systematic screening for mutations in the glycine receptor alpha2 subunit gene (GLRA2) in patients with schizophrenia and other psychiatric diseases.

The glycine receptor, which is a member of the ligand-gated ion channel superfamily, mediates synaptic inhibition in the spinal cord and other brain regions. This superfamily has been implicated in the pathogenesis of schizophrenia and other psychiatric diseases. The complete coding sequence and splice junctions of the GLRA2 gene were scanned by DOVAM-S, a form of SSCP analysis with sufficient redundancy to detect virtually all mutations. Those analyses were performed in 113 patients with schizophrenia, and in pilot studies of patients with bipolar illness, alcoholism, puerperal psychosis, autism, and attention-deficit hyperactivity disorder (533 kb total scanned sequences). We detected three sequence changes in the coding region, all resulting in silent mutations: C894T in exon 5, C1134T in exon 7, and C1476T in exon 9. These do not alter the structure or the expression of the protein. It is unlikely that mutations in the coding region and splice junction of GLRA2 gene are associated with schizophrenia and other psychiatric diseases.

Alcoholism↗
PubMed1990

Molecular analysis of human argininosuccinate lyase: mutant characterization and alternative splicing of the coding region.

Argininosuccinic acid lyase (ASAL) deficiency is a clinically heterogeneous autosomal recessive urea cycle disorder. We previously established by complementation analysis that 28 ASAL-deficient patients have heterogeneous mutations in a single gene. To prove that the ASAL structural gene is the affected locus, we sequenced polymerase chain reaction-amplified ASAL cDNA of a representative mutant from the single complementation group. Fibroblast strain 944 (approximately 1% of residual ASAL activity), from a late-onset patient who was the product of a consanguineous mating, had only a single base-pair change in the coding region, a C-283----T transition at a CpG dinucleotide in exon 3. This substitution converts Arg-95 to Cys (R95C), occurs in a stretch of 13 residues that is identical in yeast and human ASAL, and was present in both of the patient's alleles but not in 14 other mutant or 10 normal alleles. Expression in COS cells demonstrated that the R95C mutation produces normal amounts of ASAL mRNA but little protein and less than 1% ASAL activity. We observed that amplified cDNA from mutant 944 and normal cells (liver, keratinocytes, lymphoblasts, and fibroblasts) contained, in addition to the expected 5' 513-base-pair band, a prominent 318-base-pair ASAL band formed by the splicing of exon 2 from the transcript. The short transcript maintains the ASAL reading frame but removes Lys-51, a residue that may be essential for catalysis, since it binds the argininosuccinate substrate. We conclude (i) that the identification of the R95C mutation in strain 944 demonstrates that virtually all ASAL deficiency results from defects in the ASAL structural gene and (ii) that minor alternative splicing of the coding region occurs at the ASAL locus.

Argininosuccinate Lyase↗
PubMed2001

Dynamic optimization of odor representations by slow temporal patterning of mitral cell activity.

Mitral cells (MCs) in the olfactory bulb (OB) respond to odors with slow temporal firing patterns. The representation of each odor by activity patterns across the MC population thus changes continuously throughout a stimulus, in an odor-specific manner. In the zebrafish OB, we found that this distributed temporal patterning progressively reduced the similarity between ensemble representations of related odors, thereby making each odor's representation more specific over time. The tuning of individual MCs was not sharpened during this process. Hence, the individual responses of MCs did not become more specific, but the odor-coding MC assemblies changed such that their overlap decreased. This optimization of ensemble representations did not occur among olfactory afferents but resulted from OB circuit dynamics. Time can therefore gradually optimize stimulus representations in a sensory network.

Amino Acids↗
PubMedDate not supplied

[Genetics of congenital color vision defects. I. Common types of color blindness].

Normal human colour vision is based on the presence of 3 kinds of cones containing 3 different visual pigments, sensitive to short (blue), middle (green) and long (red) wavelengths. Congenital defects of colour vision are based on handicap or total loss of these pigments' function, usually a result of changes in their coding genes. The common types of colour blindness, referred to red-green axis, are present in about 8% of males and 0.44% of females. 3/4 of them are deuteranopes or deuteranomalous trichromats and 1/4 of them are protanopes or protanomalous trichromats. All of them are inherited in X-linked recessive way. The genes have been already mapped and sequenced. The cause of the great majority of their changes is nonhomologous recombination, which produces a gene deletion or creates the red-green or green-red hybrid genes. The result of that is the production of visual pigment with partly or totally changed spectral sensitivity.

Color Vision Defects↗
PubMedDate not supplied

Primary structure of influenza virus genome regions coding for polypeptides from the major antigenic sites of H3 hemagglutinin.

Nucleotide sequences for some regions of the hemagglutinin (HA) gene of influenza virus A/Leningrad/385/80 (H3N2) were analyzed. A double-stranded complementary DNA was synthesized on the influenza genome RNA in the presence of synthetic oligodeoxyribonucleotides A GCAAAAGCAGG and A GTAGAAACAAG and inserted into the Pst I-site of the pBR322 plasmid through G-C-tailing. Nucleotide sequences were determined by a solid phase modification of the Maxam and Gilbert procedure. A comparison of our data with those for influenza virus A/Bangkok/1/79, which is the nearest sequenced prototype of the strain investigated, revealed only two base changes in the variable region of the HA gene. One of them was accompanied by a change in the coded amino acid (Asp53----Tyr) located in the antigenic site E of the HA glycoprotein. There also were some point mutations in the constant region of the gene. The results obtained are discussed in terms of the evolution of "Hong Kong" influenza viruses during their circulation.

Antigens, Viral↗
PubMed1992

Cardiac hypertrophy-induced changes in mRNA levels for TGF-beta 1, fibronectin, and collagen.

Cardiac hypertrophy induced by pressure overload is accompanied by increases in the deposition of extracellular matrix (ECM) proteins. We wanted to determine in this study whether changes in mRNA coding for transforming growth factor (TGF)-beta 1, TGF-beta 3, and the ECM proteins, fibronectin and collagen, occur during the early phases of cardiac hypertrophy. Steady-state mRNA levels were determined in sham-operated and thoracic-banded hypertrophied rat myocardium from 6 h to 30 days after surgery. TGF-beta 1 mRNA increased significantly (1.7-fold vs. control) 12 h after aortic banding, decreasing to control levels by 14 days. No significant changes were observed for TGF-beta 3 message. Fibronectin mRNA levels increased twofold at day 1 and peaked to approximately threefold at day 3. Type I and III collagen mRNA expression was similar to control levels at day 1 but increased significantly 3 days after banding. Cardiac hypertrophy also resulted in an induction of mRNA for an embryonic isoform of fibronectin (EIIIA+) that is generated through alternative splicing of the gene. These findings indicate that, with myocardial hypertrophy, mRNAs for fibronectin are increased as early as 1 day after banding, which may allow for an initial increase in the production of fibronectin followed by the deposition of collagen. These increased mRNA levels for the ECM proteins are preceded by marked increases in TGF-beta 1 mRNAs.

Animals↗
PubMed1984

Changing patterns of gene expression during sporulation in yeast.

Analysis of RNAs isolated from the yeast Saccharomyces cerevisiae reveals a dramatic series of changes in protein coding sequences during sporulation. Shortly after transfer to sporulation medium, mRNAs for certain proteins are repressed while a broad array of mRNAs for other proteins is induced. Superimposed on this general increase in transcriptional activity is the very strong induction of a particular subset of heat shock mRNAs, the same subset that is induced during the normal course of oogenesis in Drosophila. At distinct times later in sporulation, two sets of abundant mRNAs are coordinately induced. Unlike the earlier changes in the message complement, these changes are unique to sporulating cells. As asci mature, one set of sporulation-specific RNAs is selectively degraded. The second set, as well as the broad array of mRNAs induced earlier in development, is retained in a highly stable and fully translatable form.

Diploidy↗
PubMed1994

Screening for mutations in the exon 26 of the apolipoprotein B gene in hypercholesterolemic Finnish families by the single-strand conformation polymorphism method.

To date, the only known apolipoprotein B (apo B) mutation causing hypercholesterolemia is the apo B 3500 Arg-->Gln or the familial defective apo B (FDB) mutation. This mutation has not been detected in the Finnish population. We have set up a systematic single-strand conformation polymorphism (SSCP) analysis-based screening method to search for other mutations in the exon 26 of the apo B gene in 21 Finnish hypercholesterolemic probands. The 7572-bp exon 26 covers half of the coding region of the gene including the DNA sequence coding for the putative low-density lipoprotein (LDL) receptor binding site on the apo B protein. Exon 26 was amplified as six 1190- to 1435-bp fragments, each of which was further split into three smaller 213- to 579-bp segments by restriction enzymes. These digestion products were run on nondenaturing polyacrylamide gels using at least three different electrophoretic conditions and autoradiographed. All previously known genetic variants in the exon 26 were detected by the SSCP method. A C-->T change at nucleotide 7064, in complete association with the XbaI site, was characterized by direct sequencing. This variant did not affect the amino acid sequence of the apo B protein. The SSCP-based procedure appears suitable for systematic screening for DNA sequence changes in large coding regions.

Apolipoproteins B↗
PubMed1985

Restricted changes in the adenovirus DNA-binding protein that lead to extended host range or temperature-sensitive phenotypes.

Human adenovirus fails to multiply efficiently in monkey cells owing to a block to late viral gene expression. Ad2hr400 through Ad2hr403 are a set of host range (hr) mutants which were selected for their ability to readily grow in these cells at 37 degrees C. The mutations responsible for this extended host range have previously been mapped to the 5' portion of the gene encoding the 72-kilodalton DNA-binding protein (DBP). DNA sequence analyses indicate that all four hr mutants contain the same alteration at coding triplet 130, which changes a histidine codon to a tyrosine codon. These results extend those of Anderson et al. (J. Virol. 48:31-39, 1983), which suggested that only this change in the DBP amino acid sequence can expand adenovirus host range to monkey cells. The hr phenotype does not appear to require phosphorylation of this tyrosine residue, since no phosphotyrosine was detected in DBP isolated from Ad2hr400-infected monkey cells. The hr mutants Ad2hr400 through Ad2hr403, however, are cold sensitive for growth in monkey cells. The mutant Ad2ts400, which was derived from Ad2hr400, represents a second class of hr mutants which can grow efficiently in monkey cells at 32.5 degrees C. The cold-resistant hr mutation of Ad2ts400 has previously been mapped to the 5' region of the DBP gene (map units 63.6 through 66). DNA sequence analysis of this region shows that this mutant contains the original hr alteration at coding triplet 130 as well as a second alteration at coding triplet 148, which changes an alanine codon to a valine codon. We suspect that the alterations at amino acids 130 and 148 change the structure of the amino-terminal domain of the DBP, allowing it to better interact with monkey cell components required for late viral gene expression. Ad2ts400 also contains a temperature-sensitive mutation which has previously been mapped to the 3' portion of the DBP gene (map units 61.3 through 63.6). Sequence analysis of this region indicates that the DBP coding triplet 413 has been altered. This change from a serine codon to a proline codon is the same alteration reported in the previously sequenced DBP mutants Ad5ts125 (W. Kruijer et al., Nucleic Acids Res. 9:4439-4457, 1981) and Ad5ts107 (W. Kruijer et al., Virology 124:425-433, 1983). Thus it appears that only a very limited number of changes in either the 5' or the 3' portion of the DBP gene can give rise to the hr or temperature-sensitive phenotypes, respectively.

Adenoviruses, Human↗
PubMed2002

Microalbuminuria modifies the mortality risk associated with electrocardiographic ST-T segment changes.

OBJECTIVES: We sought to investigate whether microalbuminuria, a proposed marker of generalized vascular damage, enhances the prognostic value of ST-T segment changes for all-cause and cardiovascular mortality in the general population. BACKGROUND: ST-T segment changes on the rest electrocardiogram (ECG) predict mortality in the general population. However, the excess risk seems to be low, particularly in nonhospitalized populations with a low cardiovascular risk profile. METHODS: In a population of 7,330 male and female subjects, a total of 89 deaths (1.2%) occurred during a median three-year follow-up. In 69 of these, the cause of death was obtained from the Central Bureau of Statistics: 25 subjects died of cardiovascular causes (36%). Using computerized Minnesota coding, ST-T segment changes were coded as 4.1-4 and 5.1-4. Microalbuminuria was defined as a urinary albumin excretion of 30 to 300 mg per 24 h. RESULTS: The combination of ST-T segment changes and microalbuminuria showed a higher hazard ratio (HR) for all-cause mortality (HR 8.6 [95% confidence interval [CI] 4.8 to 15.2, p < 0.0001), as compared with ST-T segment changes in the absence of microalbuminuria (HR 1.3 [95% CI 0.7 to 2.5]), which was independent of other cardiovascular risk factors (HR 3.3 [95% CI 1.5 to 7.1], p = 0.002). The combination showed a higher HR when only cardiovascular deaths were taken into account, as compared with all-cause mortality (HR 24.5 [95% CI 7.9 to 76.0], p < 0.0001), which also counted for ST-T segment changes alone (HR 4.4 [95% CI 1.4 to 14.5], p = 0.02). After controlling for other risk factors, the HRs were 10.4 (95% CI 2.5 to 43.6, p = 0.001) for the combination and 2.7 (95% CI 0.6 to 12.3) for ST-T segment changes alone. CONCLUSIONS: This study suggests that, in subjects with ST-T segment changes on their rest ECG, microalbuminuria could identify those at increased risk of all-cause and cardiovascular mortality.

Adult↗
PubMed1986

Sequence, evolution and differential expression of the two genes encoding variant small subunits of ribulose bisphosphate carboxylase/oxygenase in Chlamydomonas reinhardtii.

We have sequenced the two genes for the small subunit of ribulose bisphosphate carboxylase/oxygenase (Rubisco) in Chlamydomonas reinhardtii and analyzed their expression. The two genes encode variant small subunits that differ by four amino acid residues. Both genes are expressed and each is transcribed into an RNA of distinct size. The accumulation of the two RNAs changes depending on the growth conditions, so the small subunit composition of Rubisco may be expected to differ in response to the environment. The C. reinhardtii small subunit sequence is homologous to those of vascular plants or cyanobacteria, but is longer at the amino terminus and in internal positions. The number and location of the intervening sequences in the genes from C. reinhardtii and from other plants differ. In several cases, internal length differences in the polypeptide coincide with the positions of introns in the coding sequence. Thus, changes in the exon structure of the genes during evolution may have been accompanied by substantial changes in the encoded protein. The translation and splicing signals in C. reinhardtii are similar to those of other eukaryotes, but the transcription signals are less conserved and the highly biased codon usage is very unusual.

Amino Acid Sequence↗
PubMed1994

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement.

The variable (V) genes of antigen-selected antibodies are known to exhibit a higher frequency of amino acid replacement mutations in the sequences encoding the antigen-contacting complementarity-determining regions (CDRs) than in those encoding the 'structural' framework regions (FRs). Here, Bernard Chang and Paolo Casali analyse the impact of regional differences in the codon composition of human germline Ig VH and VL genes on regional differences in the frequency of replacement mutations in the gene products (i.e. the antigen-binding sites of antibody molecules). This analysis reveals that CDR and FR sequences can differ significantly in their inherent susceptibility to amino acid replacement given any single nucleotide change. Thus, the CDR sequences of all the Ig VH genes analysed comprise a higher frequency of codons susceptible to replacement mutations than would be expected for a random sequence. Conversely, the FR sequences comprise codons less susceptible to replacement mutations than expected. Random accumulation of nucleotide changes throughout the coding sequence of an Ig V-gene segment containing CDRs inherently more prone to replacement mutations than the respective FRs would inevitably yield a higher rate of amino acid replacements in the CDRs than in the FRs. This would provide a fertile structural substrate of hypervariability for antigen selection while still maintaining the structural integrity of the FRs.

Amino Acid Sequence↗
PubMed1985

Homoeotic transformations in man: implications for the mechanism of embryonic development and for the organization of epithelia.

Homoeotic transformations are substitutions of one body part for another which arise during embryogenesis or regeneration. They are well known among the Arthropoda but are not generally thought to occur in Man or other vertebrates. In this paper the occurrence and characteristics of 21 types of epithelial heterotopia and metaplasia are reviewed and it is concluded that they are fully comparable with the homoeotic transformations of the arthropods.. The transformations are concentrated in the gastrointestinal, urinary and female reproductive systems and typically appear as foci of ectopic epithelium with a sharp discontinuity of cell type at the edges of the patches. Most of the transformations occur in renewal tissues and must therefore be interpreted as changes in the states of determination (epigenetic codings) of the stem cells rather than changes between already differentiated cells. Most, but not all, of the transformations are between tissues whose precursors are neighbouring regions of a common cell sheet during early embryogenesis and which are therefore likely to have neighbouring epigenetic codings. Following the Cairns hypothesis for epithelial organization it is proposed that stem cells themselves are protected against changes in epigenetic coding but their daughter cells, normally destined to differentiate and die, are not. Homoeotic transformations may thus occur in situations in which daughter cells become promoted to stem cells which happens either during the growth phase of the organism or during tissue regeneration in the adult.

Animals↗
PubMed1993

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

Multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are dominantly inherited conditions which predispose to the development of endocrine neoplasia. Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders. Single strand conformational variants (SSCVs) in exons 7 and 8 of the RET proto-oncogene were identified in eight MEN 2A and four FMTC families. The variants were observed only in the DNA of individuals who were either affected or who had inherited the MEN2A or FMTC allele as determined by haplotyping experiments. The seven variants identified were sequenced directly. All involved point mutations within codons specifying cysteine residues, resulting in nonconservative amino acid changes. Six of the seven mutations are located in exon 7. A single mutation was found in exon 8. Variants were not detected in four MEN 2B families studied for all exon assays available, nor were they detectable in 16 cases of well documented sporadic medullary thyroid carcinoma or pheochromocytoma that were tested for exon 7 variants. Coinheritance of the mutations with disease and the physical and genetic proximity of the RET proto-oncogene provide evidence that RET is responsible for at least two of the three inherited forms of MEN 2. Neither the normal function, nor the ligand of RET are yet known. However, its apparent involvement in the development of these inherited forms of neoplasia as well as in papillary thyroid carcinoma suggest an important developmental or cell regulatory role for the protein.

Amino Acid Sequence↗
PubMed2001

High-throughput sequence identification of gene coding variants within alcohol-related QTLs.

Low initial response to alcohol has been shown to be among the best predictors of development of alcoholism. A similar phenotypic measure, difference in initial sensitivity to ethanol, has been used for the genetic selection of two mouse strains, the Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice, and for the subsequent identification of four quantitative trait loci (QTLs) for alcohol sensitivity. We now report the application of high throughput comparative gene sequencing in the search for genes underlying these four QTLs. To carry out this search, over 1.7 million bases of comparative DNA sequence were generated from 68 candidate genes within the QTL intervals, corresponding to a survey of over 36,000 amino acids. Eight central nervous system genes, located within these QTLs, were identified that contain a total of 36 changes in protein coding sequence. Some of these coding variants are likely to contribute to the phenotypic variation between ILS/ISS animals, including sensitivity to alcohol, providing specific new genetic targets potentially important to the neuronal actions of alcohol.

Alcoholism↗
PubMed2002

Automatic and controlled processing of melodic contour and interval information measured by electrical brain activity.

Most work on how pitch is encoded in the auditory cortex has focused on tonotopic (absolute) pitch maps. However, melodic information is thought to be encoded in the brain in two different "relative pitch" forms, a domain-general contour code (up/down pattern of pitch changes) and a music-specific interval code (exact pitch distances between notes). Event-related potentials were analyzed in nonmusicians from both passive and active oddball tasks where either the contour or the interval of melody-final notes was occasionally altered. The occasional deviant notes generated a right frontal positivity peaking around 350 msec and a central parietal P3b peaking around 580 msec that were present only when participants focused their attention on the auditory stimuli. Both types of melodic information were encoded automatically in the absence of absolute pitch cues, as indexed by a mismatch negativity wave recorded during the passive conditions. The results indicate that even in the absence of musical training, the brain is set up to automatically encode music-specific melodic information, even when absolute pitch information is not available.

Adult↗