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PubMed1995

Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unique substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

Demography↗
PubMed1999

The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor.

p120(ctn) is an Armadillo repeat domain protein with structural similarity to the cell adhesion cofactors beta-catenin and plakoglobin. All three proteins interact directly with the cytoplasmic domain of the transmembrane cell adhesion molecule E-cadherin; beta-catenin and plakoglobin bind a carboxy-terminal region in a mutually exclusive manner, while p120 binds the juxtamembrane region. Unlike beta-catenin and plakoglobin, p120 does not interact with alpha-catenin, the tumor suppressor adenomatous polyposis coli (APC), or the transcription factor Lef-1, suggesting that it has unique binding partners and plays a distinct role in the cadherin-catenin complex. Using p120 as bait, we conducted a yeast two-hybrid screen and identified a novel transcription factor which we named Kaiso. Kaiso's deduced amino acid sequence revealed an amino-terminal BTB/POZ protein-protein interaction domain and three carboxy-terminal zinc fingers of the C2H2 DNA-binding type. Kaiso thus belongs to a rapidly growing family of POZ-ZF transcription factors that include the Drosophila developmental regulators Tramtrak and Bric à brac, and the human oncoproteins BCL-6 and PLZF, which are causally linked to non-Hodgkins' lymphoma and acute promyelocytic leukemia, respectively. Monoclonal antibodies to Kaiso were generated and used to immunolocalize the protein and confirm the specificity of the p120-Kaiso interaction in mammalian cells. Kaiso specifically coprecipitated with a variety of p120-specific monoclonal antibodies but not with antibodies to alpha- or beta-catenin, E-cadherin, or APC. Like other POZ-ZF proteins, Kaiso localized to the nucleus and was associated with specific nuclear dots. Yeast two-hybrid interaction assays mapped the binding domains to Arm repeats 1 to 7 of p120 and the carboxy-terminal 200 amino acids of Kaiso. In addition, Kaiso homodimerized via its POZ domain but it did not heterodimerize with BCL-6, which heterodimerizes with PLZF. The involvement of POZ-ZF proteins in development and cancer makes Kaiso an interesting candidate for a downstream effector of cadherin and/or p120 signaling.

Amino Acid Sequence↗
PubMed1991

Transcriptional attenuation control of ermK, a macrolide-lincosamide-streptogramin B resistance determinant from Bacillus licheniformis.

ermK instructs bacteria to synthesize an erythromycin-inducible 23S rRNA methylase that confers resistance to the macrolide, lincosamide, and streptogramin B antibiotics. Expression of ermK is regulated by transcriptional attenuation, in contrast to other inducible erm genes, previously described, which are regulated translationally. The ermK mRNA leader sequence has a total length of 357 nucleotides and encodes a 14-amino-acid leader peptide together with its ribosome binding site. Additionally, the mRNA leader sequence can fold in either of two mutually exclusive conformations, one of which is postulated to form in the absence of induction and to contain two rho factor-independent terminators. Truncated transcription products ca. 210 and 333 nucleotides long were synthesized in the absence of induction, both in vivo and in vitro, as predicted by the transcriptional attenuation model; run-off transcription in vitro with rITP favored the synthesis of the full-length run-off transcript over that of the 210- and 333-nucleotide truncated products. Northern (RNA) blot analysis of transcripts synthesized in vivo in the absence of erythromycin indicated that transcription terminated at either of the two inverted complementary repeat sequences in the leader that were postulated to serve as rho factor-independent terminators; moreover, no full-length transcripts were detectable in the uninduced samples. In contrast, full-length (ca. 1,200-nucleotide) transcripts were only detected in RNA samples synthesized in vivo in the presence of erythromycin. Full-length transcripts formed in the absence of induction from transcriptional readthrough past the two proposed transcription terminators would fold in a way that would sequester the ribosome binding site together with the first two codons of the ErmK methylase, reducing its efficiency in translation. This feature could therefore provide additional control of expression in the absence of induction; however, such regulation, if operative, would act only secondarily, both in time and place, relative to transcriptional control. Analysis by reverse transcriptase mapping of in vivo transcripts from two primers that bracket the transcription terminator responsible for the 210-nucleotide truncated fragment supports the transcriptional attenuation model proposed and suggests further that the synthesis of the ermK message is initiated constitutively upstream of the proposed terminator but completed inductively downstream of this site.

Amino Acid Sequence↗
PubMed2025

A novel insertion/deletion in APC promotor 1B is associated with both gastric and colon polyposis.

Pathogenic variants in the APC gene are classically associated with autosomal dominant familial adenomatous polyposis (FAP), characterized by tens-to-thousands of colonic adenomatous polyps and a high-penetrance predisposition to colorectal cancer. More recently, specific PVs in the YY1 binding motif of APC promoter 1B have been associated with autosomal dominant gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), characterized by tens-to-thousands of fundic gland polyps and a predisposition to gastric cancer but which are only rarely associated with features consistent with FAP. Although management guidelines currently treat FAP and GAPPS as mutually exclusive conditions, the extent of phenotypic overlap is not well-characterized. Here, we present a multi-clinic and -laboratory collaboration reporting a previously undescribed APC promoter 1B insertion/deletion likely pathogenic variant in a family with mixed GAPPS and FAP phenotype. The family proband is a female of unspecified white ancestry. She was diagnosed with GAPPS at age 30 and, after developing gastric cancer at age 39, underwent curative gastrectomy. She is now 61 with a cumulative history of between 50 and 100 colon adenomas and recently completed subtotal colectomy. Her multi-gene panel testing in 2022 demonstrated a likely pathogenic insertion/deletion (indel) within the APC promoter 1B YY1 binding motif (APC c.-192_-191delATinsTAGCAAGGG). Review of a four-generation pedigree revealed the ages of gastric cancer presentation in the family ranged from 39-60's, with advanced gastric polyposis and prophylactic gastrectomy as early as ages 11 and 13 in the proband's daughter and nephew, respectively. Six of 10 (60%) family members known or presumed to carry the APC likely pathogenic variant underwent colectomy or hemicolectomy due to colon polyposis. The youngest known carrier in the family is a 12-year-old female, and the oldest living carrier is the proband's brother, age 66. A novel APC indel causes concomitant GAPPS and FAP presentations in this previously unreported large kindred. Mixed gastric and colon phenotypes have been rarely described in GAPPS families and the ages of presentation of gastric polyposis are strikingly young in the current family with prophylactic gastrectomies completed as early as age 11 and 13. These ages are significantly younger than the 15 years of age at which national guidelines currently recommend initiation of EGD for screening in GAPPS. Although the mechanism for this combined GAPPS-FAP phenotype is unclear, patients in this family and those with similar APC promoter 1B variants should be offered both gastric and colon cancer risk management.

Adult↗