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PubMed1989

Complex segregation analysis of dental morphological variants.

A set of 20 morphological variants of the dental crowns and four characteristics of the jaws are tested for probable mode of inheritance using the complex segregation analysis method of Morton et al. (Am. J. Hum. Genet. 23:602-611, 1971). Models tested include three two-allele single-locus models (dominant, codominant, and recessive) and a model employing the polychotomized normal distribution of liability (an additive polygenic model), with transmissibility estimated via maximum likelihood. Most of the traits studied are observed using ordinal scales with several grades, and many are tested using more than one dichotomy of their scale. These multiple analyses allow for an examination of such factors as trait incidence on the results of the statistical analysis. The results of the analysis yield propositions of major genes for 13 of the 24 traits examined. Two traits give good evidence of being polygenic in origin. The remaining nine characters present methodological problems that do not allow for a definite conclusion on their mode of inheritance at this time. The ability to test varying levels of transmissibility in the polygenic model allows for an estimation of the percentage of trait variance determined by familial factors. Estimates of transmissibility for all characters examined range from 0 to 1, with a mean of 0.36. These findings may suggest a large environmental role in the development of dental crown morphology. However, the possibility exists that difficulties in the ability to classify the expression of certain traits consistently result in overestimates of the environmental influences on the development of those characters.

Anthropology, Physical↗
PubMed1983

Biochemical and molecular analysis of naturally occurring Adh variants in Drosophila melanogaster.

The results of a detailed analysis of the biochemical and molecular basis of alcohol dehydrogenase (ADH) activity variation existing among six naturally occurring and one ethyl methanesulfonate-induced Adh variant strain of Drosophila melanogaster are presented. Significant specific activity differences exist among the strains but the majority of ADH activity variation can be accounted for by differences in levels of ADH protein. These protein level differences can, in turn, be accounted for by ADH synthesis rate variation, which positively correlates with in vivo levels of cytoplasmic Adh mRNA. The functional variability is correlated with known structural variation in and around the area of the Adh gene.

Alcohol Dehydrogenase↗
PubMed1989

Isolation and characterization of a mouse L cell variant deficient in glucocorticoid receptors.

The growth of mouse L cell fibroblasts is inhibited by glucocorticoids, and we have selected spontaneous glucocorticoid-resistant L cells in culture. One cloned variant exhibits a stable phenotype in the absence of selective conditions. This variant contains no specific glucocorticoid-binding capacity, no immunoreactive glucocorticoid receptor protein, and no detectable glucocorticoid receptor messenger RNA. A glucocorticoid-dependent reporter gene requires exogenous glucocorticoid receptor cDNA and steroid in order to be expressed in this variant. Genomic DNA analysis of the variant cell line indicates that there has been no gross alteration in receptor gene structure. These results suggest that the variant may be deficient in transcription of the glucocorticoid receptor gene.

Animals↗
PubMed1984

Polar encapsidation of adenovirus DNA: evolutionary variants reveal dispensable sequences near the left ends of Ad3 genomes.

Repeated passage of adenovirus type 3 in HeLa cells has led to a novel stock of variant genomes, characterized by deletions and substitutions of DNA sequences within the left-end 750 base pairs. This heterogeneous stock retains few if any parental genomes--the majority of variants appear viable. Analysis of viable variants with deleted sequences reveals the 182 nucleotides proximal to the left-end inverted terminal repeat (136-318 bp) are not required for Ad3 infectivity in cultured human cell lines nor for maintenance of viral DNA encapsidation polarity.

Adenoviruses, Human↗
PubMed1993

Activities of fluoroquinolone, macrolide, and aminoglycoside drugs combined with inhibitors of glycosylation and fatty acid and peptide biosynthesis against Mycobacterium avium.

Smooth- and rough-colony variants of Mycobacterium avium serovar 4 were treated with three classes of drugs. The drugs were chosen for their potential inhibitory effects on the biosynthesis of the cell envelope-associated serovar-specific glycopeptidolipid antigens. Growth was monitored radiometrically with a BACTEC 460-TB instrument, and MICs were determined for each drug. Both variants were then treated with inhibitory drugs in combination with antimicrobial agents that have demonstrated effectiveness against M. avium. No growth inhibition was observed with 6-fluoro-6-deoxy-D-glucose or avidin. Inhibitors of glycosylation, i.e., 2-deoxy-D-glucose, bacitracin, and ethambutol, were inhibitory to smooth- and rough-colony variants, whereas drugs that inhibit peptide synthesis, i.e., N-carbamyl-L-isoleucine and m-fluoro-phenylalanine, were more inhibitory for the rough-colony variant. Cerulenin, which affects fatty acid synthesis, was inhibitory for both variants, but it appeared to be more effective at inhibiting the growth of the smooth-colony variant at equivalent concentrations. Generally, when inhibitors of glycosylation were used with sparfloxacin and amikacin, a synergistic effect was observed for only the smooth variant. When drugs that affect peptide synthesis were used in combination with amikacin, a synergistic effect was observed for the rough variant, and when cerulenin was used in combination with sparfloxacin or amikacin, a synergistic effect was observed for both variants. Lipid analysis revealed that although the rough variant lacks the serovar-specific glycopeptidolipid antigens, it does possess a group of phenylalanine-isoleucine-containing lipopeptides that may explain its different susceptibility patterns to m-fluoro-phenylalanine and N-carbamyl-L-isoleucine. The significance of these results is discussed with reference to various components in the cell envelope and their importance in cell wall permeability.

Aminoglycosides↗
PubMed1995

Identification and genetic analysis of a common molecular variant of histidine-rich glycoprotein with a difference of 2kD in apparent molecular weight.

Two forms of histidine-rich glycoprotein (HRG) were detected on SDS-PAGE by silver staining and immunoblotting after isolation of the protein from pooled plasma using immuno-affinity chromatography followed by chromatography with heparin-Sepharose. Both forms were single-chain molecules and the apparent molecular weights of form 1 and form 2 were 77 kD and 75 kD respectively. Mendelian inheritance of both HRG forms was observed in four families with 24 informative meioses, strongly suggesting that the two forms are encoded by different alleles. The frequency of form 1 and form 2 in a group of 36 individuals was 0.35 and 0.65 respectively. The difference between the two molecular variants was studied by direct sequence analysis of amplified exons of the HRG gene from 6 individuals who were homozygous either for form 1 or form 2. Five amino acid polymorphisms in three different exons were observed: Ile/Thr in exon4; Pro/Ser in exon 5; His/Arg, Arg/Cys and Asn/Ile in exon 7. Analysis of these polymorphisms in 20 volunteers showed that only the Pro/Ser polymorphism at position 186 in exon 5 was coupled to the form of the HRG protein. Ser was found in form 1 and Pro in form 2. The presence of Ser at position 186 introduces a consensus sequence for a N-glycosylation site (Asn-X-Ser/Thr). By removing N-linked sugars with N-glycanase, it could be demonstrated that the difference between the two forms of HRG is caused by an extra carbohydrate group at Asn 184 in form 1.

Amino Acid Sequence↗
PubMed2026

Analysis of CYLD gene variants in 41 patients with multiple familial trichoepithelioma.

OBJECTIVE: To investigate the variants of the CYLD gene in Chinese patients with multiple familial trichoepithelioma (MFT), aiming to provide a scientific basis for genetic counseling and prenatal diagnosis, thereby creating favorable conditions for intervention treatment and improving the prognosis of patients. PATIENTS AND METHODS: Whole-exome sequencing (WES) was performed in patients from eleven families to identify candidate variants, which were subsequently confirmed by Sanger sequencing. The minigene technique was used to perform functional analyses of the variants c.2342-8C>G and c.1685-9T>G. Whole-genome sequencing (WGS) was applied in patients with negative WES results. RESULTS: All 41 patients presented with multiple papules or nodules on the nose. We identified six novel pathogenic variants and three recurrent pathogenic variants. Conversely, no gene variants were detected in four patients. The c.1685-9T>G variant caused aberrant mRNA splicing, resulting in the insertion of an 8-base intronic sequence into the mRNA and subsequent premature termination, while the variant c.2342-8C>G led to premature mRNA splicing seven bases upstream of the canonical splice site. CONCLUSIONS: This study identified six novel and three recurrent pathogenic variants in the CYLD gene among 41 patients with MFT. Comprising the largest sample size report in this field to date, this work considerably expands the mutational spectrum of the CYLD gene (currently comprising 144 variants) and carries important implications for genetic counseling.

Humans↗
PubMed1993

Assessment of autonomic nervous activity by heart rate spectral analysis in patients with variant angina.

The purpose of this study was to assess the role of the autonomic nervous system in the pathogenesis of coronary artery spasm in patients with variant angina. We evaluated cardiac sympathetic and parasympathetic activity from the power (logarithmic scale) of the low-frequency (approximately 0.04 to 0.12 Hz) and the high-frequency (approximately 0.22 to 0.32 Hz) spectral components of heart rate variability with Holter monitoring in seven patients with nocturnal variant angina and in 11 healthy men who served as control subjects. None of the patients had organic coronary artery stenosis as determined by angiography. Low-frequency and high-frequency logarithmic values were calculated for each 5-minute period from 30 minutes before to immediately before each angina attack. The logarithmic low-frequency value during the 5-to-0-minute period was greater than the low-frequency values during most of the other periods (p < 0.05 - p < 0.01). The logarithmic high-frequency values during the 10-to-5-minute and 5-to-0-minute periods were greater than those during the 30-to-25-minute period (p < 0.05 and p < 0.01, respectively). These data indicate that parasympathetic activity increased during the 10 minutes before attacks of nocturnal variant angina, whereas sympathetic activity with vagal modulation increased during the 5 minutes before such attacks. The same pattern of changes in heart rate variability was found in the absence of ST-segment elevation in patients and in control subjects. So this phenomenon was not just associated with coronary spasm and variant angina. It is suggested that circadian variation in disease activity is also associated with spontaneous attacks.

Adult↗
PubMed1997

Expression of estrogen receptors in a normal human breast epithelial cell type with luminal and stem cell characteristics and its neoplastically transformed cell lines.

Although approximately two-thirds of breast cancers are estrogen receptor (ER)-positive, only a small proportion of epithelial cells in the mammary gland express the ER. The origin of the ER-positive breast cancers is unknown. Recently, we have developed a culture method to grow two morphologically and antigenically distinguishable types of normal human breast epithelial cells (HBEC) derived from reduction mammoplasty. In this report, we studied the expression of ER in these two types of cells and their transformed cell lines. The results indicate that Type I HBEC with luminal and stem cell characteristics expressed a variant ER (approximately 48 kd) by Western blot analysis. This variant ER contains a deletion in the DNA binding domain (exon 2) as revealed by RT-PCR analysis. The lack of the DNA-binding domain of the variant ER was also confirmed by the ER-estrogen responsive element binding assay, as well as by the immunofluorescence staining of the ER using anti-ER antibodies which recognize either the C-terminal or N-terminal region. In contrast, Type II HBEC with basal epithelial phenotype are ER-negative. Simian virus 40 (SV40) transformed Type I and Type II HBEC lines also expressed the variant ER. Tumors formed in athymic nude mice by in vitro transformed tumorigenic Type I cell lines, however, expressed a high level of wild type ER which was undetectable in these cells grown in vitro before and after tumor formation. Thus, there appears to be a differential ER mRNA splicing between the in vitro and in vivo mileu.

Adult↗
PubMed1991

Cleavage by protease from Staphylococcus aureus V8: an improvement in the sequence analysis of human hemoglobin variants.

Protease from Staphylococcus aureus V8 cleaves either at glutamic residues or at both aspartic and glutamic residues, depending on the experimental conditions. In structural analyses of human hemoglobin variants, the specificity of this enzyme is of considerable interest to localize substitutions occurring in medium or large size peptides as it cleaves in smaller fragments which may be unambiguously characterized. It may also recognize the replacement of an acidic residue by the corresponding amide, or vice versa, avoiding protein sequence analysis. The various aspects of the use of protease V8 are illustrated by the study of four alpha chain hemoglobin variants concerning peptides alpha T-9 and alpha T-12b.

Amino Acid Sequence↗
PubMed1997

Cloning and functional analysis of a polymorphic variant of the ovine Mel 1a melatonin receptor.

We have isolated a novel variant of the Mel 1a melatonin receptor from an ovine PT cDNA library. Relative to the reported sequence for the Mel 1a melatonin receptor there are 8 changes in the DNA sequence. Only 3 of these result in amino acid substitutions, one in extracellular loop 3 and two in the carboxy-terminal tail. We have designated the novel variant of the sheep Mel 1a receptor Mel 1a(beta), and correspondingly the previously reported variant Mel 1a(alpha). As minor changes in the primary amino acid sequence of G-protein-coupled receptors can influence their functional characteristics we have accordingly characterized this novel variant of the Mel 1a melatonin receptor. This melatonin receptor displays high affinity binding and inhibits the cAMP second messenger pathway in transfected L-cells demonstrating that this receptor is fully functional. PCR analysis shows Mel 1a(beta) is present in several breeds of sheep and suggests that the Mel 1a(beta) receptor was established early in the evolution of the sheep species.

Animals↗
PubMed1993

Why are some genetic diseases common? Distinguishing selection from other processes by molecular analysis of globin gene variants.

Various processes (selection, mutation, migration and genetic drift) are known to determine the frequency of genetic disease in human populations, but so far it has proved almost impossible to decide to what extent each is responsible for the presence of a particular genetic disease. The techniques of gene and haplotype analysis offer new hope in addressing this issue, and we review relevant studies of three haemoglobinopathies: sickle cell anaemia, and alpha and beta thalassaemia. We show how for each disease it is possible to recognize a pattern of regionally specific mutations, found in association with one or a few haplotypes, that is best explained as the result of selection; other patterns are due to population migration and genetic drift. However, we caution that such conclusions can be drawn in special circumstances only. In the case of the haemoglobinopathies it is possible because a selective agent (malaria) was already suspected, and the investigations could be carried out in relatively genetically homogenous populations whose migratory histories are known. Moreover, some data reviewed here suggest that gene conversion and the haplotype composition of a population may affect the frequency of a mutation, making interpretation of gene frequencies difficult on the basis of standard population genetics theory. Hence attempts to use the same approaches with other genetic diseases are likely to be frustrated by a lack of suitably untrammelled populations and by difficulties accounting for poorly understood genetic processes. We conclude that although this combination of molecular and population genetics is successful when applied to the study of haemoglobinopathies, it may not be so easy to apply it to the study of other genetic diseases.

Africa, Northern↗
PubMed1993

Detection of missense mutations by single-strand conformational polymorphism (SSCP) analysis in five dysfunctional variants of coagulation factor VII.

Five unrelated subjects with dysfunctional coagulation factor VII (FVII) were studied in order to identify missense mutations affecting function. Exons 2 to 8 and the intron-exon junctions of their FVII genes were amplified from peripheral white blood cell DNA by PCR and screened by SSCP analysis. DNA fragments showing aberrant mobility were sequenced. The following mutations were identified: in case 1 (FVII:C < 1%, FVII:Ag 18%) a heterozygous A to G transition at nucleotide 8915 in exon 6 results in the amino acid substitution Lys-137 to Glu near the C-terminus of the FVIIa light chain; in case 2 (FVII:C 7%, FVII:Ag 47%) a heterozygous A to G transition at nucleotide 7834 in exon 5 results in the substitution of Gln-100 by Arg in the second EGF-like domain; in case 3 (FVII:C 20%, FVII:Ag 76%) a homozygous G to A transition at nucleotide position 6055 in exon 4 was detected resulting in substitution of Arg-79 by Gln in the first EGF-like domain; in case 5 (FVII:C 10%, FVII:Ag 52%) a heterozygous C to T transition at nucleotide position 6054 in exon 4 also results in the substitution of Arg79, but in this case it is replaced by Trp; case 4 (FVII:C < 1%, FVII:Ag 100%) was homozygous for a previously reported mutation (G to A) at nucleotide position 10715 in exon 8, substituting Gln for Arg at position 304 in the protease domain. Cases 1, 2 and 5 evidently have additional undetected mutations.

Amino Acid Sequence↗
PubMed1997

A survey of the newborn populations in Belgium, Germany, Poland, Czech Republic, Hungary, Bulgaria, Spain, Turkey, and Japan for the G985 variant allele with haplotype analysis at the medium chain Acyl-CoA dehydrogenase gene locus: clinical and evolutionary consideration.

Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is an inborn error of fatty acid metabolism. It is one of the most frequent genetic metabolic disorders among Caucasian children. The G985 allele represented 90% of all the variant alleles of the MCAD gene in an extensive series of retrospective studies. To study the distribution of the G985 allele, newborn blood samples from the following countries were tested; 3000 from Germany (1/116). 1000 each from Belgium (1/77). Poland (1/98), Czech Republic (1/240). Hungary (1/168), Bulgaria (1/91), Spain (1/141). Turkey (1/216), and 500 from Japan (none). The frequency is shown in parentheses. The haplotype of G985 alleles in 1 homozygote and 57 heterozygote samples were then analyzed using two intragenic MCAD gene polymorphisms (Iaq1 and GT-repeat). The result indicated that only 1 of the 10 known haplotypes was associated with the G985 mutation, suggesting that G985 was derived originally from a single ancestral source. We made a compilation of the G985 frequencies in these countries and those in nine other European countries studied previously. The G985 distribution was high in the area stretching from Russia to Bulgaria in the east and in all northern countries in western and middle Europe, but low in the southern part of western and middle Europe. The incidence among ethnic Basques appeared to be low. This distribution pattern and the fact that all G985 alleles belong to a single haplotype suggest that G985 mutation occurred later than the delta F508 mutation of the CFTR, possibly in the neolithic or in a later period, and was brought into Europe by IndoEuropean-speaking people. The panEuropean distribution of the G985 allele, including Slavic countries from which patients with MCAD deficiency have rarely been detected, indicates the importance of raising the level of awareness of this disease.

Acyl-CoA Dehydrogenases↗
PubMed1995

Analysis of envelope sequence variants suggests multiple mechanisms of mother-to-child transmission of human immunodeficiency virus type 1.

In order to elucidate the molecular mechanisms involved in human immunodeficiency virus type 1 (HIV-1) mother-to-child transmission, we have analyzed the genetic variation within the V3 hypervariable domain and flanking regions of the HIV-1 envelope gene in four mother-child transmission pairs. Phylogenetic analysis and amino acid sequence comparison were performed on cell-associated viral sequences derived from maternal samples collected at different time points during pregnancy, after delivery, and from child samples collected from the time of birth until the child was approximately 1 year of age. Heterogeneous sequence populations were observed to be present in all maternal samples collected during pregnancy and postdelivery. In three newborns, viral sequence populations obtained within 2 weeks after birth revealed a high level of V3 sequence variability. In contrast, V3 sequences obtained from the fourth child (diagnosed at the age of 1 month) displayed a more restricted heterogeneity. The phylogenetic analysis performed for each mother-child sequence set suggested that several mechanisms may potentially be involved in HIV-1 vertical transmission. For one pair, child sequences were homogeneous and clustered in a single branch within the phylogenetic tree, consistent with selective transmission of a single maternal variant. For the other three pairs, the child sequences were more heterogeneous and clustered in several separate branches within the tree. In these cases, it appeared likely that more than one maternal variant was responsible for infection of the child. In conclusion, no single mechanism can account for mother-to-child HIV-1 transmission; both the selective transmission of a single maternal variant and multiple transmission events may occur.

Adult↗
PubMed1980

The mechanism of antigenic drift in influenza viruses: analysis of Hong Kong (H3N2) variants with monoclonal antibodies to the hemagglutinin molecule.

Monoclonal antibodies to the hemagglutinin molecule of the Hong Kong variant, Mem/1/71 (H3N2), influenza virus were used to study antigenic drift in the H3N2 subtype of influenza viruses. Antigenic variants of Mem/1/71 (H3N2) were selected after a single passage of the virus in chick embryos in the presence of monoclonal antibody. The variants showed a marked reduction in the ability to react with the monoclonal antibody used in selection. The monoclonal antibodies could be divided into three groups based on their reactions with the variants, providing evidence for at least three nonoverlapping antigenic areas on the hemagglutinin molecule. Amino acid analysis of tryptic peptides of the hemagglutinin from these variants showed that a single amino acid substitution in the heavy polypeptide chain (HA1) of the hemagglutinin molecule accounted for the reduced antibody interactions, and that variants from each group exhibited sequence changes in different areas of the molecule. Sequence changes were also detected in the HA1 polypeptides of naturally occurring H3N2 variants, but in most cases the changes in the monoclonal antibody selected variants were different from the field strains. Antigenic analysis showed that most of the variants selected with monoclonal antibody could not be distinguished from parental viruses with heterogeneous sera, suggesting that they are probably epidemiologically irrelevant. One variant, however, could be distinguished from parental virus with heterogeneous sera. This variant showed a change in sequence at residue 144 of the HA1 polypeptide from glycine in the parent to aspartic acid in the variant. Similar substitutions have been found in naturally occurring variants at this position. These studies suggest that some amino acid substitutions are more important than other for producing viruses with epidemiological potential. Antigenic analysis of naturally occurring H3N2 strains with monoclonal antibodies established that two variants co-circulated in 1968; Hong Kong/1/68 being distinguishable from Aichi/2/68 in at least two antigenic areas. It would appear that there may have been two separate lineages of H3N2 viruses, Hong Kong/1/68 giving rise to variants in England and Aichi/2/68 to variants in USA and Australia.

Amino Acid Sequence↗