R. Thomas Taggart

Age-Gender Influence on the Rate-Corrected QT Interval and the QT-Heart Rate Relation in Families With Genotypically Characterized Long QT Syndrome

OBJECTIVES We sought to analyze age-gender differences in the rate-corrected QT (QTc) interval in the presence of a QT-prolonging gene. BACKGROUND Compared with men, women exhibit a longer QTc interval and an increased propensity toward torsade de pointes. In normal subjects, the QTc gender difference reflects QTc interval shortening in men during adolescence. METHODS QTc intervals were analyzed according to age (< 16 or > or = 16 years) and gender in 460 genotyped blood relatives from families with long QT syndrome linked to chromosome 11p (KVLQT1; n = 199), 7q (HERG; n = 208) or 3p (SCN5A; n = 53). RESULTS The mean QTc interval in genotype-negative blood relatives (n = 240) was shortest in men, but similar among women, boys and girls. For genotype-positive blood relatives, men exhibited the shortest mean QTc interval in chromosome 7q- and 11p-linked blood relatives (n = 194), but not in the smaller 3p-linked group (n = 26). Among pooled 7q- and 11p-linked blood relatives, multiple regression analysis identified both genotype (p < 0.001) and age-gender group (men vs. women/children; p < 0.001) as significant predictors of the QTc interval; and heart rate (p < 0.001), genotype (p < 0.001) and age-gender group (p = 0.01) as significant predictors of the absolute QT interval. A shorter mean QT interval in men was most evident for heart rates < 60 beats/min. CONCLUSIONS In familial long QT syndrome linked to either chromosome 7q or 11p, men exhibit shorter mean QTc values than both women and children, for both genotype-positive and -negative blood relatives. Thus, adult gender differences in propensity toward torsade de pointes may reflect the relatively greater presence in men of a factor that blunts QT prolongation responses, especially at slow heart rates.

Human pepsinogen C (progastricsin) polymorphism: Evidence for a single locus located at 6p21.1-pter ☆ ☆☆

A series of six clones containing the entire human pepsinogen C gene (PGC) was identified in a cosmid vector library by using cDNA and oligonucleotide probes. The 10.7-kb PGC gene includes nine exons and exhibits a high degree of sequence identity (60%) with the functionally related pepsinogen A genes. The predicted amino acid sequence was identical with the partial amino-terminal and carboxyl-terminal sequences of purified pepsinogen C. An informative restriction fragment length polymorphism was detected with several restriction enzymes and involved an insertion or deletion of 100 bp of intron sequence located between exons 7 and 8. Evidence that there is only a single PGC gene in humans is presented. The PGC gene and the prolactin gene were regionally localized to 6p21.1-pter by analysis of mouse X human somatic cell hybrids.

Carboxyl terminal glycine extended progastrin (gastrin-G) in gastric antral mucosa of patients with gastric or duodenal ulcer and in gastrinomas.

Recently, carboxyl terminal glycine extended progastrin (gastrin‐G), the immediate biosynthetic precursor of amidated gastrin, was found in human gastric antral mucosa. To investigate the nature of gastrin amidation in pathophysiological conditions, we examined gastrin and gastrin‐G levels and their molecular forms in gastric antral mucosa of healthy controls and patients with gastric or duodenal ulcer and in gastrinomas. There were no significant differences between controls and gastric or duodenal ulcer patients in antral gastrin and gastrin‐G levels, the ratio of gastrin‐G to gastrin and the pattern of their molecular forms. In contrast, gastrin and gastrin‐G levels and the ratio of gastrin‐G to gastrin in gastrinomas were much higher than those in antral mucosa of controls or ulcer patients. The predominant molecular form of gastrin‐G was different between two Zollinger‐Ellison syndrome (ZES) cases. These results suggest that there are no significant differences between healthy controls and patients with gastric or duodenal ulcer in the nature of gastrin amidation, and that the nature of gastrin amination in gastrinomas is different from that in normal gastrointestinal tissues.

A Highly Informative Polymorphism of the Pepsinogen C Gene Detected by Polymerase Chain Reaction

Human pepsinogen, the inactive precursor of pepsin, comprises two biochemically and immunologically distinct groups of isozymogens; namely PGA and PGC. PGA has been localized to 11ql3 and PGC to 6p21.1→pter.1–4 Previous studies demonstrated that a region of the human pepsinogen C gene contained a restriction fragment length polymorphism by Southern blot analysis of genomic DNA with a PGC cDNA clone. This RFLP involved a 100 bp insertion or deletion of intron sequence located between exons 7 and 8. Analysis of families segregating for this polymorphism indicated that there is a single human PGC gene located on the short arm of chromosome 6.

Human pepsinogen A (PGA): an informative gene complex located at 11q13

SummaryHuman pepsinogen (PGA) exhibits extensive polymorphism that can be detected both at the protein and the DNA level. We describe here two restriction fragment length polymorphisms, EcoRI and BglII, which provide for the detection of three of the most common PGA haplotypes (A, B, and C) in the United States population. The relationship of these polymorphisms to each PGA haplotype was determined by analysis of DNA from individuals exhibiting the corresponding protein phenotypes and by analysis of a series of human × mouse somatic cell hybrids containing the individual chromosome 11 homologous from heterozygous individuals exhibiting the AB and AC protein phenotypes. The use of the BglII polymorphism in combination with previously described EcoRI polymorphism provides a very informative marker of 11q13.

Detection of a polymorphism within the pepsinogen C gene with PCR: construction of a linkage map around PGC from 6p11-6p21.3.

An insertion/deletion polymorphism between exons 7 and 8 of the pepsinogen C gene (PGC), previously detectable with Southern analysis, was formatted for detection with PCR. Alleles were rapidly typed by UV irradiation of ethidium bromide-stained agarose gels. Whereas Southern analysis revealed two alleles, the smaller fragments generated with PCR allowed the resolution of three alleles that were previously scored as a single allele and increased the heterozygosity of the system from 0.20 to 0.53. After a set of reference families was genotyped with the PCR-based polymorphism, a linkage map around the PGC gene on chromosome 6 was constructed. This included the HLA cluster and the highly informative D6S223 locus. PGC lies 22 cM proximal to HLA-DPB and between D6S5 and D6S4 at distances of 4.5 and 13.1 cM, respectively.

Origins of the Multiple Cathepsin E Transcripts Observed in Human Gastric Mucosa and Gastric Adenocarcinoma

We previously reported the cloning and sequence analysis of human gastric cathepsin E (CTSE) cDNA clones. The cDNA clones were isolated from a gastric adenocarcinoma recombinant library using a set of complementary nondegenerate 18mer oligonucleotide probes specific for a 6 residue sequence surrounding the first active site region of all previously characterized human aspartic proteinases.1 Northern analysis of poly (A+) RNA isolated from CTSE producing gastric adenocarcinoma cell line revealed three transcripts (3.6, 2.6 and 2.1 kb). The multiple CTSE transcripts are a unique finding among aspartic proteinases and may result from several potential causes including; multiple genes, rearranged genes, alternative initiation of transcription, alternative splicing or alternative polyadenylation. In the present study, we examined additional CTSE cDNA clones in an attempt to determine the origin of multiple transcripts observed in gastric adenocarcinoma. We present here evidence that two major CTSE transcripts (2.6 and 2.1 kb) result from alternative polyadenylation of the primary CTSE transcript.