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Biomedical subjects

A W Eriksson

Publications and source records attributed to A W Eriksson.

At least 55 records · Page 3Linked to original sources
PubMed1989

Family and population studies on the human pepsinogen A multigene family.

Human pepsinogen A (PGA) displays highly polymorphic isozymogen patterns after polyacrylamide gel electrophoresis and activity staining. The patterns differ with respect to the presence and the relative intensity of the individual fractions. Family studies strongly suggest that these isozymogen patterns are encoded by allelic haplotypes, encompassing different numbers and types of PGA genes. In this paper, we confirm the essential features of this multigene model. We establish the relationship between the haplotypes and the corresponding isozymogen patterns by determination of the PGA polymorphism at both the DNA and the protein level in 117 Dutch individuals, 60 of whom were unrelated. The combination of HindIII and EcoRI restriction fragment length polymorphisms (RFLPs) has enabled us to define different haplotypes, which are shown to segregate within families. Most genes are characterized by their specific EcoRI fragments. The HindIII RFLP is in strong linkage disequilibrium with PGA genes showing strong expression of the relevant isozymogen. Although a general picture of the relationship between genotypes and phenotypes is emerging, there are exceptions, suggesting that rare haplotypes evolve by unique crossover events.

DNA↗
PubMed1989

The human alpha-amylase multigene family consists of haplotypes with variable numbers of genes.

Polymorphic amylase protein patterns have suggested the presence in the human genome of various haplotypes encoding these allozymes. To investigate the genomic organization of the human alpha-amylase genes, we isolated the pertinent genes from a cosmid library constructed of DNA from an individual expressing three different salivary amylase allozymes. From the restriction maps of the overlapping cosmids and a comparison of these maps with the restriction enzyme patterns of DNA from the donor and family members, we were able to identify two haplotypes consisting of very different numbers of salivary amylase genes. The short haplotype contains two pancreatic genes (AMY2A and AMY2B) and one salivary amylase gene (AMY1C), arranged in the order 2B-2A-1C, encompassing a total length of approximately 100 kb. The long haplotype spans about 300 kb and contains six additional genes arranged in two repeats, each one consisting of two salivary amylase genes (AMY1A and AMY1B) and a pseudogene lacking the first three exons (AMYP1). The order of the amylase genes within the repeat is 1A-1B-P1. All genes are in a head-to-tail orientation except AMY1B, which has the reverse orientation with respect to the other genes. Analysis of somatic cell hybrids confirmed the presence of these short and long haplotypes. Furthermore, we present evidence for the existence of additional haplotypes in the human population and propose a general model for the evolution of the human alpha-amylase multigene family. A general designation 2B-2A-(1A-1B-P)n-1C can describe these haplotypes, n being 0 and 2 for the short and the long haplotypes presented in this paper, respectively.

Biological Evolution↗
PubMed1989

Nucleotide sequence comparison of five human pepsinogen A (PGA) genes: evolution of the PGA multigene family.

To unravel the genetic basis for the pepsinogen A (PGA) protein polymorphism, we have isolated and characterized a number of PGA genes, distinguishable by polymorphic EcoRI fragments of 12.0, 15.0, and 16.6 kb. Using a HindIII or AvaII polymorphism, we can discriminate between different 15.0 (15.0 and 15.0*) and 12.0 (12.0s and 12.0l) genes, respectively. The coding sequences of a 15.0 and a 16.6 gene were determined, together with considerable stretches of the 5'- and 3'-flanking regions and introns. The genes were demonstrated to encode Pg5 and Pg4, respectively. Because substitutions in codons 43 and 207 appeared to be critical in the determination of the encoded proteins, we sequenced only these regions in the two 12.0 genes and the 15.0* gene. On the basis of these partial sequences, we assume that these genes encode Pg3. In the evolutionary model of the PGA gene cluster presented here, the 12.0 genes arose by an unequal, but homologous crossover. The results of sequence analysis of the second intron of the 12.0s, 12.0l, 15.0, and 16.6 genes suggest that the two 12.0 genes have arisen from two different crossover events.

Amino Acid Sequence↗
PubMed1989

The glomerular sieving of pepsinogen A and C in man.

Pepsinogen A (PGA) and pepsinogen C (PGC) are negatively charged, low molecular weight (LMW) proteins with a striking difference in renal handling: PGA (molecular weight 43,500 daltons) shows a high fractional excretion while the fractional excretion of PGC (molecular weight 40,500 daltons) is low, presumably due to tubular reabsorption. As these data suggest a high glomerular sieving of pepsinogens, we assessed the glomerular sieving coefficient (GSC) of PGA, PGC and several other proteins from their renal extractions. For this purpose blood samples were obtained simultaneously from the aorta (A) and right renal vein (V) in nine patients undergoing an elective heart catheterization. After correction of A-V differences for diuresis with the A-V difference of transferrin, GSCs (+/- SEM) for PGA and PGC were 0.90 +/- 0.14 and 0.85 +/- 0.17, respectively, GSC of beta 2-microglobulin being 0.90 +/- 0.12. For albumin and IgG, known to have a low GSC, low values were found. It is concluded that the GSC of a LMW protein in man can be calculated from both its A-V difference over the kidney and the A-V difference of an inert marker with a GSC of 1, provided they are corrected by the A-V difference of an inert marker with a GSC of 0. Our results demonstrate that PGA and PGC are almost freely filtered through the glomerular basement membrane despite their size and negative net molecular charge.

Adult↗
PubMed1989

The renal metabolism of pepsinogen A and C in man.

Pepsinogen A (PGA) and pepsinogen C (PGC) are almost identical low molecular weight proteins with marked differences in renal handling. PGA is present in large amounts while PGC is almost absent in the urine of healthy subjects. Whether the amount of PGA in the urine represents the total amount of PGA that is extracted, is unknown. We, therefore, assessed the renal metabolism of PGA and PGC by measuring PGA, PGC and creatinine concentrations in the aorta and the right renal vein, and in the urine from patients undergoing elective heart catheterization. The renal extractions of PGA and PGC were not significantly different from the extraction of creatinine: 22%, 18% and 24%, respectively. Sixty-eight percent of PGA and 98% of PGC extracted from the circulation were metabolized by the kidney, and fractional metabolism was closely related to the fractional reabsorption of PGA and PGC from the glomerular filtrate. It is concluded that the kidney metabolizes PGA and PGC. The fractional metabolism of PGA and PGC can be calculated from the fractional reabsorption. Further studies on the renal handling of pepsinogens are warranted as they may provide information on factors affecting renal metabolism of low molecular weight proteins.

Absorption↗
PubMed1988

Cloning and sequencing of rhesus monkey pepsinogen A cDNA.

The complete nucleotide sequence of Rhesus monkey (Macaca mulatta) pepsinogen A (PGA) cDNA was determined from two partially overlapping cDNA clones, covering the whole coding sequence and part of the flanking sequences. The nucleotide and deduced amino acid sequences were compared to known PGA sequences from other species. The degree of similarity with human PGA appeared to be 96% at the nucleotide sequence level and 94% at the amino acid sequence level. In the coding region the divergence was highest in the activation peptide. The amino acid sequence similarity between Japanese monkey (Macaca fuscata) PGA and Rhesus monkey PGA was shown to be 99%. Using the cDNA as probe in Southern hybridization of EcoRI-digested human and Rhesus monkey genomic DNAs, PGA patterns with inter-individual differences were observed. The hybridization patterns are compatible with the existence of a PGA multigene family in both species.

Amino Acid Sequence↗
PubMed1988

Inbreeding and genetic disease in Sottunga, Finland.

The contribution of inbreeding to the prevalence of recessive genetic diseases in the Aland Island parish of Sottunga is investigated. Genealogical data for 3,030 individuals spanning up to 15 generations were used to estimate inbreeding. This small island community shows a low average inbreeding value of .0031 for the period 1725-1975. A cohort analysis shows that inbreeding increased from 1750 to 1900, when maximum inbreeding for those born in Sottunga reached .0057. A sharp decline in inbreeding occurred thereafter. Individuals with island-born parents made the largest contributions to inbreeding in all time periods compared to those with one or two migrant parents. These trends are consistent with changing migration patterns and isolate breakdown in Aland since 1900. An analysis of pedigree development demonstrates that remote consanguinity contributed more to inbreeding through time than close consanguinity. Both the number of common ancestors and the number of paths of relationship between spouses increased dramatically through time, the latter at a much faster rate. The contribution to average inbreeding per path, however, diminished rapidly through time. This analysis indicates that inbreeding does not account for the high incidence of autosomal recessive disorders, such as tapetoretinal disease, found in the parish.

Consanguinity↗
PubMed1988

Founder effect and genetic disease in Sottunga, Finland.

Pedigree data are analyzed in order to determine the factors responsible for the high frequencies of certain genetic disorders in an isolated Swedish-speaking population of Finland's A land archipelago. The founders of Sottunga are identified, and the genetic contributions of each founder to descending birth cohorts are estimated. Founders born before 1700 have far more descendants in the contemporary gene pool than do more recent founders. However, because of migration and depopulation since 1900, the expected genetic contributions of the early founders to the present-day population are similar to those of later founders. A descendant in the contemporary population has a 2% chance of having inherited a particular gene from the founder who makes the largest single contribution to the gene pool. This corresponds approximately to a 2% probability of inheriting an autosomal dominant disease gene from this founder. Given an average inbreeding coefficient of 0.0016, the probability of inheriting two recessive disease genes from this founder is 0.000032. The incidence of autosomal dominant von Willebrand disease in Sottunga is greater than 10% while that of autosomal recessive tapetoretinal disease is 1.5%. We conclude, therefore, that the high frequencies of these diseases are not due to the disproportionate genetic contribution of one or a few particular founders. It is more likely that these disease genes occurred in high frequency in the initial population or were introduced repeatedly through time.

Finland↗
PubMed1988

Statistical analysis of the migration component of genetic drift.

Statistical methods are introduced for analysis of the migration component of genetic drift, i.e., of the stochastic changes that affect allele frequencies during migration between local groups. Attention focuses on alpha M, a parameter that measures the extent to which this component of drift departs from the ideal of independent random sampling, and which can be interpreted as a measure of the extent to which migration is kin-structured. It is shown that alpha M can be estimated from genetic data, even in the absence of information about the genealogical relationships of migrants, and Monte-Carlo simulations are used to approximate the sampling distribution of the estimator under the null hypothesis of independent random sampling. Application of these methods to data from the Aland Islands, Finland, shows that the migration pattern there is consistent with the hypothesis of independent random sampling.

Finland↗
PubMed1988

Genomic structure and evolution of the human pepsinogen A multigene family.

A human cosmid library was screened with a pepsinogen A (PGA) cDNA probe, yielding 18 clones with (parts of) one, two or three PGA genes. By aligning these cosmids a restriction map of a PGA gene quadruplet was obtained in which the four genes are arranged in a highly ordered fashion in a head-to-tail orientation. Using the length in kilobases of the large polymorphic EcoRI fragment of the PGA genes, this quadruplet can be described as 15.0-12.0-12.0-16.6. An AvaII polymorphism allowed us to identify the two PGA haplotypes of the individual whose DNA had been cloned in the cosmid library to be a gene triplet and a gene quadruplet. By comparing the restriction maps of the central 12.0 genes in these multiplets to those of the flanking 15.0 and 16.6 genes, we postulate that these central genes arose from unequal but homologous crossing over between two 15.0-16.6 gene pairs. This hypothesis provides for the creation of a variety of haplotypes by additional cross overs and mutations. Southern blots of family and population material supports the existance of at least five common PGA haplotypes, including a single-gene haplotype, giving rise to a large number of different EcoRI patterns. The single PGA gene is probably the reciprocal crossing over product. Comparison between the DNA and protein polymorphisms suggests further micro-heterogeneity in the different PGA haplotypes.

Biological Evolution↗
PubMed1988

No predictive value of GC phenotypes for HIV infection and progression to AIDS.

The genetic polymorphism of group-specific component (GC) was investigated with isoelectric focusing in 351 homosexual men at risk for HIV infection, 96 male patients with AIDS, and 86 heterosexual controls. No significant differences in GC phenotype distribution were seen between controls and any of the at risk groups or patients, neither between HIV-Ab-positive/Ag-negative and HIV-Ab-positive/Ag-positive homosexual men nor between HIV-Ab-positive/Ag-positive homosexual men and AIDS patients, suggesting that the GC system is not involved in the infective susceptibility or progression of HIV infection to AIDS-related complex and AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Immunohistochemical localization of pepsinogen A and C containing cells in Barrett's oesophagus.

No data are available on the localization of Pepsinogen A (PGA = PG I) and Pepsinogen C (PGC = PG II) positive cells in Barrett's epithelium. Endoscopic biopsy specimens were taken from the columnar epithelium from 23 patients (n = 93), and in addition from the cardia from eight healthy control subjects (n = 38). The tissue was stained by the immunoperoxidase technique with specific anti-pepsinogen antisera, and double immunostained for PGA and PGC. In the Barrett's epithelium PGA was found in 28 out of 93 biopsy specimens (30.1%) and PGC in 55 out of 93 (59.1%). Chief cells always stained both for PGA- and PGC +. PGA + and PGC + cells were found each in 100% of the biopsy specimens with fundic type epithelium, in 21.7% and 70.7% of biopsy specimens with junctional type, in 0% and 26.1% of biopsy specimens with specialized epithelium and in 12.5% and 43.5% of biopsy specimens with mixed junctional/specialized features respectively. Dysplastic epithelium stained always negatively with both anti-pepsinogen antisera. In most control cardia biopsy specimens PGA as well as PGC were demonstrable; occasionally clear mucous glands were PGA - and PGC+. It is concluded that pepsinogen-containing cells can be accurately identified in the Barrett's epithelium; their presence seems related to the histological cell type. Identification of pepsinogen positive cells may contribute to a more accurate morphological classification of the Barrett's epithelium.

Adolescent↗
PubMed1988

Discrepancies between gastric mucosal and urinary pepsinogen A patterns and in vitro synthesis and secretion of human pepsinogen.

The relationship between electrophoretic pepsinogen A (PGA) patterns from urine and gastric mucosa was studied in healthy volunteers and in patients with various gastric disorders. Discrepancies between urinary and gastric PGA patterns were found in 63.3% of the individuals. In 9% of the subjects with these discrepancies, the phenotype class in urine was different from that in gastric mucosa. The differences were found in all diagnostic groups. The highest frequency of differences was found in patients with gastric ulcer. The differences were not related to the serum PGA level. More than 80% of the differences were caused by a lower relative intensity of pepsinogen A fraction 5 (Pg5) in urine than in gastric mucosa. The possible origin of differences in PGA isozymogen patterns was studied by organ culture of gastric biopsies. In vitro synthesis and secretion of pepsinogens were studied by electrophoresis and autoradiography. The synthesis rate of PGA in biopsies of 1-2 mm diameter was 40-100 ng/hr. Posttranslational modification of PGA isozymogens was demonstrated. Pg2 and part of Pg4 probably are secondary products of Pg3 and Pg5, respectively. In some individuals the secretion rate of Pg3 was low compared to the other isozymogens. The conversion of Pg3 into Pg2 and the differential secretion of the isozymogens may explain some of the discrepancies between gastric and urinary PGA patterns.

Autoradiography↗
PubMed1988

Twinning rate in Scandinavia, Germany and The Netherlands during years of privation.

Twinning rates were studied in Swedes, Aland Islanders, Finns, Germans, and Dutch during years of starvation when death rates were two to three times higher than average. In contrast to the situation among some animals, this study suggests that nutrition above a certain threshold is unimportant for human reproduction, including twinning. The twinning rates for these different populations display marked temporal differences, but low values in the twinning rate are not consistently associated with periods of epidemics, famine, or similar nutritional stress. After years of privation and/or separation of spouses, a rapid "catch-up effect" can often be seen in the twinning rates, as well as marriage and birth rates. Psychoendocrine factors and interparental immunological conditions that may be involved in this phenomenon are discussed.

Female↗
PubMed1988

Renal handling of pepsinogens A and C in man.

1. Fractional excretions of pepsinogens A and C in the urine were investigated in 21 healthy subjects and in 38 patients with chronic renal insufficiency. In eight of the healthy subjects fractional excretions were measured again after oral administration of omeprazole for 9 days. 2. The mean fractional excretion of pepsinogen A was 27.6% (range 4.4-73.9%) in healthy subjects and remained unchanged after omeprazole administration. In patients with renal failure the mean fractional excretion of pepsinogen A was 37.9% (range 7.0-81.9%). The mean fractional excretion of pepsinogen C was 1.0% (range 0.04-6.8%) in healthy subjects and decreased after omeprazole. In patients with chronic renal diseases a sharp rise in fractional excretion of pepsinogen C was observed once glomerular filtration rate was less than 40 ml/min. 3. Fractional excretion of pepsinogen A was unexpectedly high for a negatively charged protein with a molecule mass of 40,000 daltons. This might be explained by the presence of the positively charged activation peptide. Furthermore, pepsinogen C seemed to be almost entirely reabsorbed from the glomerular filtrate and a tubular reabsorption maximum appeared to be present. Pepsinogen C may, therefore, be a new marker of tubular function. The cause of the remarkable difference in tubular handling of two quite similar low-molecular-mass proteins remains to be elucidated.

Adult↗
PubMed1988

Differential expression of pepsinogen isozymogens in a patient with Barrett esophagus.

The pepsinogen A (PGA) isozymogens in the gastric mucosa and Barrett epithelium of a female patient with Barrett esophagus were studied on different occasions during a 3-year period by electrophoretic analysis of in vivo steady-state pepsinogen in biopsies by activity staining in combination with variant specific monoclonal antibodies and of de novo synthesized pepsinogen by autoradiography. In Barrett epithelium only one (Pg3) or two (Pg3 and Pg5) primary PGA gene products were detected, whereas in gastric mucosal biopsies three (Pg3, Pg4 and Pg5) primary gene products were demonstrated on all occasions. These differences strongly suggest differential expression/activation of individual gene numbers in the PGA gene cluster in Barrett esophagus and are in line with the preneoplastic nature of this condition. The mechanism behind this deregulation is currently under investigation by cell biology and molecular genetic techniques.

Aged↗
PubMed1988

Linkage relationships and gene order around the locus for X-linked retinoschisis.

X-linked recessive retinoschisis (RS) is a hereditary disorder with variable clinical features. The main symptoms are poor sight; radial, cystic macula degeneration; and peripheral superficial retinal detachment. The disease is quite common in Finland, where at least 300 hemizygous males have been diagnosed. We used nine polymorphic DNA markers to study the localization of RS on the short arm of the X chromosome in 31 families comprising 88 affected persons. Two-point linkage results confirmed close linkage of the RS gene to the marker loci DXS43, DXS16, DXS207, and DXS41 and also revealed close linkage to the marker loci DXS197 and DXS9. Only one recombination was observed between DXS43 and RS in 59 informative meioses, giving a maximum lod score of 13.87 at the recombination fraction .02. No recombinations were observed between the RS locus and DXS9 and DXS197 (lods between 3 and 4), but at neither locus was the number of informative meioses sufficient to provide reliable estimates of recombination fractions. The most likely gene order on the basis of multilocus analysis was Xpter-DXS85-(DXS207,DXS43)-RS-DXS41-DXS 164-Xcen. Because multilocus linkage analysis indicated that the most probable location of RS is proximal to DXS207 and DXS43 and distal to DXS41, these three flanking markers are the closest and most informative markers currently available for carrier detection.

Female↗