A. W. Eriksson

Reliable Classification of Six Pi M Subtypes by Separator Isoelectric Focusing

For the first time, segregation of three common PiM alleles in family material is verified by application of separator isoelectric focusing. A new nomenclature system for the Pi M subtypes is used, whereby the common subtypes are designated according to their physicochemical properties; the most anodal type is called Pi M1, the intermediary one Pi M2, and the most cathodal variant Pi M3 (previously called Pi M2). Pi gene frequencies from Finnish, Dutch and Black populations are presented. The PiM2 allele was rather high in Finns (0.12) but low (0.04) in the West African Bozo. The PiM3 was found with a frequency of 0.13 in Dutch, 0.08 in Finns and 0.02 in Bozo. A previous Finnish sample was retested with the new subtyping method and the six-subtype distribution was found to be in good Hardy-Weinberg equilibrium. The validity of the Pi polymorphism for population genetics, linkage analysis and parentage testing is discussed.

Clinical significance of pepsinogen A isozymogens, serum pepsinogen A and C levels, and serum gastrin levels

Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (<25 μg/l), a low serum pepsinogen A/pepsinogen C ration (<1.5), and a high serum gastrin level (> 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ration less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes. Cancer 59:952‐958, 1987.

Fanconi anaemia cells are not uniformly deficient in unhooking of DNA interstrand crosslinks, induced by mitomycin C or 8-methoxypsoralen plus UVA

SummaryFanconi anaemia (FA) cells are extremely sensitive to crosslinking agents, e. g. mitomycin C, but only moderately sensitive to trimethylpsoralen plus UVA. Evidence has been reported suggesting that there is a deficient DNA crosslink repair mechanism in FA cells, but others failed to confirm this conclusion using other methods and other crosslinking agents. We reinvestigated the mitomycin C and 8-methoxypsoralen crosslink repair in FA cells with a high sensitivity to mitomycin C. Although an essentially similar methodology was used to that previously described, no difference between the control and FA cell strains was observed, neither for mitomycin C- nor for 8-methoxypsoralen-induced crosslinks.

Erythrocyte superoxide dismutase deficiency in Fanconi's anaemia established by two independent methods of assay.

Erythrocyte superoxide dismutase (SOD; E.C.1.15.1.1) levels were quantitated in human haemolysates, both by an immunological technique and by an activity assay. The erythrocyte SOD activity level in a group of seven Fanconis anaemia patients was significantly decreased (27%, on the average) compared to a control group of nineteen healthy individuals. The fact that both the activity per antigenic unit and the electrophoretic mobility of the erythrocyte SOD was normal indicates that the deficiency in these Fanconis anaemia patients is most probably not due to a mutation in the structural gene for the enzyme but more likely due to a disturbed mechanism regulating the SOD level in the erythrocyte.

α1-Antitrypsin: Common Subtypes of Pi M

More than 20 different alleles are so far known at the Pi locus, corresponding to a total variant phenotype frequency of about 10% in most western Europeans. The common phenotype Pi M constitutes the remaining major group. Now it has been possible to identify three subtypes M1, M1M2 and M2, corresponding to the gene products of two common alleles PiM1 and PiM2, segregating as autosomal codominant alleles. Preliminary gene frequencies are reported for eight populations, the PiM2 frequency varying from 0.20 in Maris (USSR) to 0.02 in Bantus (Kenya).

Unusual response to bifunctional alkylating agents in a case of Fanconi anaemia.

SummaryChromosomal breakage frequencies were determined in Fanconi anaemia (FA) blood cultures treated with various concentrations of the polyfunctional alkylating agents mitomycin C, diepoxybutane, and cis-platinum(II)-diammine-dichloride, for which FA cells have a characteristic hypersensitivity. At concentrations that hardly affected control cultures, three out of four patients tested exhibited a concentration-dependent increase of cells with aberrant chromosomes, with a concomitant increase in the number of chromosomal aberrations per aberrant cell. The fourth patient, a 22-year-old male, was exceptional because with all three clastogens only 40% of his cultured cells exhibited a typical concentration-dependent response, while 60% of his cells responded like those from normal healthy controls. The possible nature and significance of this unusual response is discussed.

Genomic structure and evolution of the human pepsinogen A multigene family

SummaryA 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.

Assignment of human pepsinogen A locus to the q12-pter region of chromosome 11

SummaryA 0.9 kb cDNA fragment, corresponding to a large part of Rhesus monkey pepsinogen A mRNA, was used as probe for the chromosomal localization of the human pepsinogen A gene(s) using human-rodent somatic cell hybrids. Southern blot analysis of 14 human-Chinese hamster and three human-mouse cell hybrids, strongly indicates that the human PGA locus is on chromosome 11. The human-mouse hybrids, containing a translocation involving chromosome 11, allow sublocalization to the region q12-pter.

Choroideremia: close linkage to DXYS1 and DXYS12 demonstrated by segregation analysis and historical-genealogical evidence.

Linkage studies using restriction fragment length polymorphisms were conducted in the X‐linked disorder, choroideremia, designated TCD for Progressive Tapeto‐Choroidal Dystrophy. Previously demonstrated close linkage with locus DXYS1 was confirmed (lod 11.44 at 0 recombination distance). In addition, locus DXYS12 was found to be closely linked with TCD (lod 3.31 at 0 recombination distance). The disease mainly occurs in three large kindreds in remote Northern Finland. While formal genealogical proof is lacking, all presently living (more than 80 affected males and 120 carrier females) probably originate from a common founder couple born in 1644 and 1646, twelve generations ago. All 36 patients and 48 carriers tested from the three kindreds had the same haplotype (TCD/DXYS1, llkb/DXYS12,1.6kb). Given that at least 105 female meioses transmitting TCD have occurred since 1650 in these kindreds, extremely close linkage between TCD, DXYS1 and DXYS12 is suggested. The above haplotype is a very useful diagnostic tool in these TCD families. We suggest that our historical‐genealogical approach to linkage analysis may be possible elsewhere in similar isolated populations.

Genetic mapping of 12 marker loci in the Xp22.3-p21.2 region

SummaryTo provide a more precise genetic map of the p22.3–p21.2 region on the short arm of the human X chromosome, we performed multilocus linkage studies in an expanded database including 31 retinoschisis families and 40 normal families. Twelve loci from this region were examined. Although significant lod scores were observed between various pairs of markers by two-point linkage analysis, the confidence limits were found to be broad. The most likely gene order on the basis of multilocus analysis was Xpter-DXS89-DXS85-DXS16-(DXS207, DXS43)-DXS274-(DXS41, DXS92)-ZFX-DXS164-Xcen. All other alternative orders were excluded by odds of at least 40∶1.