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PubMed2005

Tandem repeat copy-number variation in protein-coding regions of human genes.

BACKGROUND: Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles. RESULTS: Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters; observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% (218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins (p = 0.882). An association with the Gene Ontology term 'protein-binding' remained significant after covariate adjustment and correction for multiple testing. Combining this analysis with previous experimental evaluations of tandem repeat polymorphism, we estimate the approximate mean frequency of tandem repeat polymorphisms in human proteins to be 6%. Because 13.9% of the polymorphisms were not a multiple of three nucleotides, up to 1% of proteins may contain frameshifting tandem repeat polymorphisms. CONCLUSION: Around 1 in 20 human proteins are likely to contain tandem repeat copy-number polymorphisms within coding regions. Such polymorphisms are not more frequent among defense-response proteins; their prevalence among protein-binding proteins may reflect lower selective constraints on their structural modification. The impact of frameshifting and longer copy-number variants on protein function and disease merits further investigation.

Frameshift Mutation↗
PubMed1995

Body image disturbance in body dysmorphic disorder and eating disorders. Obsessions or delusions?

At this time, the question posed by this article's title--body image disturbance in body dysmorphic disorder and eating disorders: obsessions or delusions?--is probably best answered "both." Both disorders appear to be characterized by obsessional and delusional thinking. In addition, it is likely that their nondelusional and delusional variants constitute a single disorder encompassing a spectrum of insight, with the entire spectrum characterized by obsessional thinking. This view represents a considerable departure from DSM-III-R, in which the psychotic disorders were encapsulated in a separate section of the manual and considered different disorders from their nonpsychotic variants. The one exception was the mood disorders, which were acknowledged to have psychotic variants that were classified in the manual's "nonpsychotic" section. In DSM-IV, on the basis of emerging empirical evidence about the dimensional nature of the psychotic/nonpsychotic boundary, the dichotomy between delusional and nondelusional disorders is less clear. The double coding allowed for BDD acknowledges that BDD and its delusional disorder variant may constitute a single disorder; that allowed for OCD acknowledges that OCD may be delusional. With regard to eating disorders, however, DSM-IV is surprisingly silent, perhaps because delusional preoccupations are less common than in BDD. These issues also may apply to other disorders. Like BDD, hypochondriasis is classified as a somatoform disorder, with its delusional variant a type of delusional disorder, somatic type. Do the delusional and nondelusional variants of hypochondriasis constitute the same disorder? Do other types of somatic delusional disorder, such as parasitosis and olfactory reference syndrome (the belief that one emits a foul body odor) have nondelusional variants? It is likely that a number of disorders span a spectrum from delusional to nondelusional thinking, with unlimited shades of gray in between. Future research may indicate that obsessional disorders such as BDD, anorexia, OCD, and hypochondriasis, as well as other disorders such as major depression, should have qualifiers or subtypes--for example, "with good insight," "with poor insight," and "with delusional (or psychotic) thinking"--with an implied continuum of insight embraced by a single disorder. Such an approach, which scatters psychosis throughout the nomenclature, ultimately may be shown to be a more valid and clinically useful classification approach. Answers to these questions will not only improve our classification system but also may have important treatment implications. For example, the preliminary finding that delusional BDD responds preferentially to SRIs but not to neuroleptic agents contradicts conventional wisdom about the treatment of psychosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1990

Temperature sensitive synthesis of transfer RNAs in vivo in Saccharomyces cerevisiae.

Dictyostelium discoideum tRNA genes can be expressed efficiently in vivo in yeast, and transcription products are processed to mature tRNAs. However, primary transcripts of a variant tRNA(Val)(UAC) gene are processing deficient under standard growth conditions (30 degrees C), due to a slightly altered 5' flanking region. A stable extended amino acid acceptor stem, which seems to be required to compensate a G5-G68 mismatch, cannot form. This mismatch destabilizes secondary and probably tertiary structures to such an extent that recognition of processing enzyme(s) under normal conditions (30 degrees C) is impaired. Growing yeast cells at reduced temperature (22 degrees C) can phenotypically complement the processing defect. This observation provides a new concept for the temperature dependent expression of protein coding genes which carry a nonsense codon. Translation of corresponding messages can be controlled by products of a temperature sensitive su-tRNA gene. We successfully tested this concept with two amber suppressors derived from a tRNA(Glu)(UUC) gene from D. discoideum. One of the variant tRNA genes codes for a product with a destabilized amino acid acceptor stem. Primary transcripts of this particular su-tRNA(Glu)(CUA) gene are processed only at reduced growth temperatures and consequently function as temperature sensitive suppressors only under these conditions.

Base Sequence↗
PubMed2003

Screening of human primary melanocytes of defined melanocortin-1 receptor genotype: pigmentation marker, ultrastructural and UV-survival studies.

Recent population studies have demonstrated an association with the red-hair and fair-skin phenotype with variant alleles of the melanocortin-1 receptor (MC1R) which result in amino acid substitutions within the coding region leading to an altered receptor activity. In particular, Arg151Cys, Arg160Trp and Asp294His were the most commonly associated variants seen in the south-east Queensland population with at least one of these alleles found in 93% of those with red hair. In order to study the individual effects of these variants on melanocyte biology and melanocytic pigmentation, we established a series of human melanocyte strains genotyped for the MC1R receptor which included wild-type consensus, variant heterozygotes, compound heterozygotes and homozygotes for Arg151Cys, Arg160Trp, Val60Leu and Val92Met alleles. These strains ranged from darkly pigmented to amelanotic, with all strains of consensus sequence having dark pigmentation. UV sensitivity was found not to be associated with either MC1R genotype or the level of pigmentation with a range of sensitivities seen across all genotypes. Ultrastructural analysis demonstrated that while consensus strains contained stage IV melanosomes in their terminal dendrites, Arg151Cys and Arg160Trp homozygote strains contained only stage II melanosomes. This was despite being able to show expression of tyrosinase and tyrosinase-related protein-1 markers, although at reduced levels and an ability to convert exogenous 3,4-dihydroxyphenyl-alanine (DOPA) to melanin in these strains.

Alleles↗
PubMed2006

Molecular cloning and chromosomal localization of the Bombyx Sex-lethal gene.

We cloned Bm-Sxl, an orthologue of the Drosophila melanogaster Sex-lethal (Sxl) gene from embryos of Bombyx mori. The full-length cDNAs were of 2 sizes, 1528 and 1339 bp, and were named Bm-Sxl-L and Bm-Sxl-S, respectively. Bm-Sxl-L consists of 8 exons and spans more than 20 kb of genomic DNA. The open reading frame (ORF) codes for a protein 336 amino acids in length. Bm-Sxl-S is a splice variant that lacks the second exon. This creates a new translation start 138 nucleotides downstream and an ORF that codes for 46 amino acids fewer at the N-terminus. Linkage analysis using an F2 panel mapped Bm-Sxl to linkage group 16 at 69.8 cM. We isolated 2 BACs that include the Bm-Sxl gene. With BAC-FISH we located Bm-Sxl cytogenetically on the chromosome corresponding to linkage group 16 (LG16) at position >68.8 cM.

Alternative Splicing↗
PubMed1994

No structural mutation in the dopamine D2 receptor gene in alcoholism or schizophrenia. Analysis using denaturing gradient gel electrophoresis.

OBJECTIVE: To examine the dopamine D2 receptor (DRD2) gene coding sequences for abnormalities associated with schizophrenia or alcoholism and thereby help to resolve the controversy surrounding the reported association of alcoholism with a restriction fragment length polymorphism located close to the DRD2 gene. DESIGN: Mutational analysis of complete DRD2 gene coding sequences by denaturing gradient gel electrophoresis followed by direct nucleotide sequencing of detected variants. SETTING: Patients and controls from clinical and epidemiologic collections in the United States and Europe. PATIENTS: A total of 253 unrelated individuals, including 106 patients with schizophrenia, 113 with alcoholism, and 34 controls. For alcoholism we included patients from previously published series in which an association of illness with allele A1 was reported (Taql site 3' to the DRD2 gene) and from other published series in which nonconfirmations of this association were reported. Nearly all persons examined were white. MAIN OUTCOME MEASURES: Frequency of nonsilent variations in DRD2 gene DNA sequences in the different diagnostic groups. RESULTS: We found three infrequent DNA variants that predict altered amino acid sequence of the receptor. None of these is associated with either alcoholism or schizophrenia. CONCLUSION: No structural coding abnormalities in the DRD2 gene are present in alcoholism or schizophrenia.

Alcoholism↗
PubMed2001

Characterization of a novel synGAP isoform, synGAP-beta.

We cloned a cDNA encoding a novel synGAP, synGAP-d (GenBank(TM) accession number ), from a rat brain cDNA library. The clone consisted of 4801 nucleotides with a coding sequence of 3501 nucleotides, encoded a protein consisting of 1166 amino acids with >99% homology with 1092 amino acid overlaps to synGAP, and contained a 13-nucleotide insertion to the previously reported synGAP mRNAs, which suggested that the clone was a splice variant of synGAP. We also found that there are at least seven variants in the 3' portion of the synGAP mRNA and that they encoded five different protein isoforms. The coding sequence of these C-terminal variants were classified into alpha1, alpha2, beta1, beta2, beta3, beta4, and gamma, and synGAP-d was classified as the beta1 form. The previously reported synGAPs (synGAP-a, -b, and -c and p135synGAP) can be classified as the alpha1 isoform. All isoforms were expressed specifically in the brain. Unexpectedly, the beta isoform, which lacks a C-terminal PSD-95-binding motif ((S/T)XV), was more restricted to the postsynaptic density fraction than the motif-containing alpha1 isoform. The beta isoform did not interact with PSD-95 but specifically interacted with a nonphosphorylated alpha subunit of Ca(2+)/calmodulin-dependent protein kinase II through its unique C-terminal tail.

Aging↗
PubMed2003

Melanocortin-3-receptor gene variants in morbid obesity.

BACKGROUND: Linkage and knock-out mice studies suggest that the melanocortin-3-receptor (MC3R) is a candidate gene for obesity. OBJECTIVE: To evaluate whether MC3R mutations underlie morbid obesity. SUBJECTS AND METHODS: MC3R coding and 5(')-flanking regions were sequenced in 48 subjects and the detected variants genotyped in 252 morbidly obese (BMI>/=40 kg/m(2)) Finns. Gel shifts were used to examine whether a mutation in the putative promoter alters GATA-factor binding. RESULTS: Three common MC3R variants were found: a 17C>A variant, changing Thr6-->Lys in 16%, a 241G>A variant changing Val81-->Ile in 15%, and a -239A>G substitution in the GATA binding site in 21% of the subjects. Four other variants were detected in the 5(') flanking region. Frequencies of the three common variants did not differ between obese and contol subjects. Among the obese, the 17C>A and 241G>A variants were coinherited and associated with increased insulin-glucose ratios (P<0.05) and leptin levels (P<0.05). GATA-4 bound efficiently to wild type oligonucleotide, but only weakly to the oligonucleotide with the -239A>G mutation. CONCLUSIONS: MC3R gene variants are common and do not explain human morbid obesity. These variants associated with subtle changes in onset of weight gain, hyperleptinemia and insulin-glucose ratios. The -239A>G mutation abolishes binding of GATA-4 to the MC3R promoter region.

Adult↗
PubMed1991

Identification of verotoxin type 2 variant B subunit genes in Escherichia coli by the polymerase chain reaction and restriction fragment length polymorphism analysis.

A set of synthetic oligonucleotide primers was designed for use in a polymerase chain reaction protocol to specifically detect the B subunit genes in vtx2ha and vtx2hb, which code for the production of the VT2 (Shiga-like toxin II) variant cytotoxins VT2v-a and VT2v-b, respectively. An additional set of primers amplified a fragment common to the B subunits of the VT2 and the VT2 variant genes. Subsequent restriction endonuclease digestion of this amplicon permitted prediction of specific VT2 and variant genotypes on the basis of predetermined restriction fragment length polymorphisms. Genotypes of 21 VT2-producing strains of Escherichia coli were determined using this polymerase chain reaction-restriction fragment length polymorphism procedure. Four strains contained B subunit target sequences only for VT2 genes, 9 strains contained sequences only for VT2v-a genes, and 3 strains contained sequences only for VT2v-b. For genes in combination, one strain contained B subunit genes for both VT2 and VT2v-a and two strains contained B subunit genes for VT2 and VT2v-b. Two strains of E. coli O91:H21 contained both VT2v-a and VT2v-b B subunit genes. The VT2 reference strain of E. coli, E32511, was found to contain the targeted sequences from both VT2 and VT2v-a genes, whereas the recombinant E. coli, pEB1, possessed only that of the VT2 gene. The specific activities of extracellular VT2 determined in HeLa cells ranged from 0.3 to 41.7 TCD50 per microgram of protein in strains carrying the VT2 gene target and from 0 to 50.0 TCD50 per microgram of protein in strains carrying only the VT2 variant target (TCD50 is the tissue culture dose by which 50% of the cells were affected), suggesting that phenotypic expression does not correlate with genotype.

Animals↗
PubMed1991

The opacity proteins of Neisseria gonorrhoeae strain MS11 are encoded by a family of 11 complete genes.

Variants of Neisseria gonorrhoeae MS11 show distinct colony morphologies because of the expression of a class of surface components called opacity (Opa, PII) proteins. Southern analyses combined with molecular cloning of genomic DNA from a single variant of MS11 has identified 11 opa genes contained in separate loci. These opa genes code for distinct opacity proteins which are distinguishable at their variable domains. The opa gene analyses were also extended to divergent variants of MS11. These studies have shown that, during in vitro and in vivo culture, 10 of the 11 opa genes did not undergo significant change in their primary sequence. However, in these variants, one gene (opaE) underwent non-reciprocal inter-opa recombinations to generate newer Opa variants. Phylogenic analysis of the opa gene sequences suggests that the opa gene family have evolved by a combination of gene duplication, gene replacement and partial inter-opa recombination events.

Amino Acid Sequence↗
PubMed1994

Characterization of a variant glucose-6-phosphate dehydrogenase from the south Indian population.

Glucose-6-phosphate dehydrogenase (G6PD) is coded by a gene on the X-chromosome. Earlier studies have shown that the South Indian population has a high incidence of this enzyme deficiency. The electrophoretic mobility, pH optimum and the Km values for G6PD from normal and variant individuals were identical. However, the specific activity of the variant enzyme was 8 times less compared to the value of the normal enzyme. Western blot analysis of partially purified G6PD from normal and variant individuals performed using equal amounts of total protein showed that the variant protein was 3 times less in concentration. Similar analysis performed using protein corresponding to equal enzyme activity units in the normal and variant samples showed that the variant enzyme was 2.25 times less efficient compared to the normal enzyme. RNA dot blot analysis using full length G6PD cDNA probe (PGDT5B, a kind gift from Prof. L Luzzatto) revealed that lymphocytes from normal and variant individuals had equal amounts of G6PD specific mRNA.

Female↗
PubMed2005

[Mutational analysis of BRCA1 and BRCA2 genes in early-onset breast cancer patients in Shanghai].

OBJECTIVE: To investigate the prevalence of BRCA1 and BRCA2 mutations among early-onset breast cancer patients in Shanghai. METHODS: Fifty patients unselected for family history, who were diagnosed with breast cancer before the age of 40 years were analyzed. Among them, 13 patients have at least one first-degree relative affected with breast cancer. Mutation screening of BRCA1 and BRCA2 was performed in the whole coding sequence through Denaturing High Performance Liquid Chromatography (DHPLC) and subsequent DNA direct sequencing. RESULTS: Six deleterious mutations, including 2 novel frameshift mutations (3449insA, 5587-1del8) and 2 novel splice-site mutations (IVS17-1G > T, IVS21 + 1G > C) in BRCA1 were identified. Two deleterious mutations detected in BRCA2, including one frameshift mutation (5950delCT) and one novel missense mutation (5911G > C), all occurring on exon 11 adjacently. Additional 12 novel sequence variants were also detected including one unclassified variant and 7 intronic variants in BRCA1, and 4 novel intronic variants in BRCA2, all causing no alteration of amino acid coding. The prevalence of BRCA1 and BRCA2 mutations in the patients with early-onset breast cancer was 12% and 4%, respectively. CONCLUSION: Four novel mutations in BRCA1 and one novel mutation in BRCA2 may be mutations characterized of early-onset breast cancer in Chinese population. Germline mutations in BRCA2 may contribute less than mutations in BRCA1 to early-onset breast cancer in Shanghai. These data contribute to information on spectrum of BRCA gene in Chinese population and also offer a recommended screening mode for clinical genetic testing programme in China.

BRCA1 Protein↗
PubMed2002

Kangaroo--a pattern-matching program for biological sequences.

BACKGROUND: Biologists are often interested in performing a simple database search to identify proteins or genes that contain a well-defined sequence pattern. Many databases do not provide straightforward or readily available query tools to perform simple searches, such as identifying transcription binding sites, protein motifs, or repetitive DNA sequences. However, in many cases simple pattern-matching searches can reveal a wealth of information. We present in this paper a regular expression pattern-matching tool that was used to identify short repetitive DNA sequences in human coding regions for the purpose of identifying potential mutation sites in mismatch repair deficient cells. RESULTS: Kangaroo is a web-based regular expression pattern-matching program that can search for patterns in DNA, protein, or coding region sequences in ten different organisms. The program is implemented to facilitate a wide range of queries with no restriction on the length or complexity of the query expression. The program is accessible on the web at http://bioinfo.mshri.on.ca/kangaroo/ and the source code is freely distributed at http://sourceforge.net/projects/slritools/. CONCLUSION: A low-level simple pattern-matching application can prove to be a useful tool in many research settings. For example, Kangaroo was used to identify potential genetic targets in a human colorectal cancer variant that is characterized by a high frequency of mutations in coding regions containing mononucleotide repeats.

Base Pair Mismatch↗
PubMed1996

Complete coding region of the new HLA-DQB1*0612 allele, obtained by RT-PCR.

A novel HLA-DQB1 allele was detected by oligotyping in the Bubi population of Equatorial Guinea. In order to characterize the new allelic variant, a RT-PCR method which permitted the cloning of its complete coding region was designed. With this method, we have determined the nucleotide sequence of the new DQB1*0612 allele, related to *0604 and *0609 but differing from them at polymorphic codon 70. A proposal for the improvement of the sequencing strategies of HLA class II alleles is made.

Alleles↗
PubMed1990

Phenotypic and molecular biological analysis of human butyrylcholinesterase variants.

Our laboratory has recently shown that several variant forms of human butyrylcholinesterase, associated with unusual sensitivity to succinylcholine, are caused by specific mutations within the structural DNA coding for this enzyme. Atypical (dibucaine-resistant) butyrylcholinesterase is caused by a point mutation at nucleotide position 209(GAT-- greater than GGT), which changes aspartate 70 to glycine. One fluoride-resistant variant family has a point mutation at nucleotide 728(ACG-- greater than ATG), which changes threonine 243 to methionine. Another type of fluoride-resistant variant has a point mutation at nucleotide 1169(GGT-- greater than GTT), which changes glycine 390 to valine. One type of silent phenotype is due to a frame-shift mutation at nucleotide position 351(GGT-- greater than GGAG). A polymorphic site at nucleotide position 1615 (GCA/ACA), coding for Ala/Thr, accounts for the quantitative K-variant, which causes an approximate one-third reduction of activity, if Thr occupies that position at codon 539. Examples are given to illustrate the advantages of using a combination of the new DNA analytical techniques, including: the use of allele-specific probes, with the standard serum cholinesterase phenotyping methods. More accurate typing of patients with certain variants is now possible; pedigree analysis will be aided by the improved methodology.

Alleles↗
PubMed2004

Identification and characterization of a novel form of the human L-dopa decarboxylase mRNA.

L-Dopa decarboxylase (DDC) has been cloned from several species and was shown to undergo alternative splicing within its 5'-untranslated and coding regions. In this report, we describe a novel splice variant of DDC mRNA in human tissue, lacking exons 10-15 of the full-length transcript but including an alternative exon 10. The isolated alternative human DDC cDNA (alt-DDC) was cloned from human placenta, and was found to be of the neuronal type. Northern blot analysis indicated that the alt-DDC transcript is expressed in high levels in human kidney. Our results demonstrate the detection of a new alternative splicing event within the coding region of the human DDC mRNA, further suggesting that the single copy human DDC gene undergoes complex processing leading to the formation of multiple mRNA isoforms.

Alternative Splicing↗
PubMed1997

Assignment of the Y4 receptor gene (PPYR1) to human chromosome 10q11.2 and mouse chromosome 14.

The human and mouse genes for the neuropeptide Y4 receptor have been isolated, sequenced, and shown to contain no introns within the coding region of the gene. Nonisotopic in situ hybridization and interspecific mouse backcross mapping have localized the genes to human chromosome 10q11.2 and mouse chromosome 14. Five nucleotide variants, which do not alter the protein sequence, have been identified within the coding region of the human receptor gene. The human Y4 subtype is most closely related to the Y1-receptor subtype (42%), suggesting that it evolved from an ancestral Y1-like receptor via an RNA-mediated transpositional event.

Animals↗
PubMed1990

The influence of GAP promoter variants on hirudin production, average plasmid copy number and cell growth in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae has been engineered to synthesize and secrete desulfato-hirudin (hirudin), a thrombin inhibitor from the leech Hirudo medicinalis. The synthetic gene coding for hirudin was expressed constitutively under the control of four size-variants of the yeast glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) and cloned into a 2 mu based multicopy yeast vector. The constitutive action of the four promoter variants was confirmed by demonstrating that the expression and secretion of hirudin is growth-related. The different efficiencies of the promoter variants not only affected hirudin expression but also led to changes in several cellular parameters, such as cell growth, average plasmid copy number and plasmid stability. The observed changes show that yeast cells establish a specific equilibrium for each promoter variant. We conclude, that the adjustment of cellular parameters in response to the expression levels of a heterologous protein is regulated by two counteracting selective forces: (1) the need for complementation of the auxotrophic host marker by the plasmid-encoded selection gene which, in the case of dLEU2, requires several plasmid copies; and (2) a selective advantage of cells with a lower copy number enabling them to escape the burden of heterologous protein production.

Base Sequence↗