Alpha-1-antitrypsin (PI) subtypes in Russians and Poles.

alpha-1-antitrypsin (PI) subtypes were studied in Poles and Russians. The frequencies of the PI alleles were similar in the two populations, with the exception of the Z allele, whose frequency was significantly lower in Poles. The M3 allele frequency, which is highly heterogeneous in European populations, has medium frequencies in Poles and Russians.     

Alpha-1-antitrypsin: Evidence for a fifth PI M subtype and a new deficiency allele PI*ZAugsburg

Summary The phenotypes of the protease inhibitor (PI) alpha-1-antitrypsin have been analyzed by isoelectric focusing on polyacrylamide gels. With improved resolution by a modified procedure it was possible to demonstrate a fifth PI^*M suballele. The bands of PI M5 are located between PI M1 and PI M3. In addition, a further deficiency allele similar to PI^*Z was found in a female patient with obstructive pulmonary disease. This variant was provisionally named PI Zaugsburg (PI Zaug). Family data confirm a simple codominant mode of inheritance for PI Zaug.Dr. W. Jahn has met with a fatal accident on June 20th, 1985 while this paper was in press. This paper is dedicated to his memory     

PI*E Tripoli: a new allele in the alpha-1-antitrypsin system.

Genetic variants of the human serum alpha 1-antitrypsin (PI system) were analyzed in a population sample of 110 unrelated Libyans. Four common PI M variants and 3 rare ones, including a new anodal variant designated PI E Tripoli (PI ET) were identified. The estimated allele frequencies were: PI*M1 = 0.623; PI*M2 = 0.205; PI*M3 = 0.132; PI*M4 = 0.018; PI*ET = 0.005; PI*S = 0.005, and PI*T = 0.014.     

Segregation distortion of the alpha 1-antitrypsin Pi Z allele.

alpha 1-antitrypsin (alpha 1AT) of the Pi type Z is associated with two diseases: pulmonary emphysema and cirrhosis of the liver. We report 23 families with both parents heterozygous for the PiZ allele, characterized from our own analysis and from world literature sources. All families were identified through members expressing disease. From the extended pedigrees, 18 backcross families (parents with Pi types MM and MZ) were identified. Analysis of the backcross families reveals a significant increase in Pi MZ offspring (.73) among families where the male is heterozygous. The distortion is not detected among families where the female is heterozygous. Among the matings where both parents are heterozygous, we found 0.43 Pi ZZ from families where one or more members expressed hepatic cirrhosis, and 0.40 Pi ZZ for total families studied. This contrasts to the 0.25 Pi ZZ expected, but is consistent with the distortion observed in backcross matings. The implications of various statistical approaches are discussed, and we point out why our findings differ from previous reports. We suggest a possible biological explanation residing in the fertilization process.     

Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele.

We have investigated the molecular basis of 15 new alpha 1-antitrypsin (alpha 1AT) variants. Phenotyping by isoelectric focusing (IEF) was used as a screening method to detect alpha 1AT variants at the protein level. Genotyping was then performed by sequence analysis of all coding exons, exon-intron junctions, and the hepatocyte-specific promoter region including exon Ic. Three of these rare variants are alleles of clinical relevance, associated with undetectable or very low serum levels of alpha 1AT:the PI*Q0saarbruecken allele generated by a 1-bp C-nucleotide insertion within a stretch of seven cytosines spanning residues 360-362, resulting in a 3' frameshift and the acquisition of a stop codon at residue 376; a point mutation in the PI*Q0lisbon allele, resulting in a single amino acid substitution Thr68(ACC)-->Ile(ATC); and an in-frame trinucleotide deletion delta Phe51 (TTC) in the highly deficient PI*Mpalermo allele. The remaining 12 alleles are associated with normal alpha 1AT serum levels and are characterized by point mutations causing single amino acid substitutions in all but one case. This exception is a silent mutation, which does not affect the amino acid sequence. The limitation of IEF compared with DNA sequence analysis, for identification of new variants, their generation by mutagenesis, and the clinical relevance of the three deficiency alleles are discussed.     

Alpha-1-antitrypsin (Pi) subtypes in the Spanish Basque provinces

Alpha-1-antitrypsin subtypes were studied in resident (644) and native (222) individuals from the Spanish Basque Country. The gene frequencies were similar to those in other Spanish populations but the isolated valley of Arratia deviated significantly with increased frequencies of the M2 and M3 alleles and a decrease of the M1 allele.     

Alpha-1-antitrypsin (protease inhibitor) phenotypes and longevity

We have tested the hypothesis that the protease inhibitor phenotypes MZ and MS are disadvantageous and reduce survival by comparing the prevalence of these phenotypes in a group of 707 very old people (hospital patients) with the prevalences reported in younger populations of blood donors. The MS and MZ phenotypes appear to be no less common among those who have survived to old age, but a highly significant difference was found in the occurrence of the M subtypes. The M1 type was more common in the elderly, and the M heterozygotes were less common than would be predicted from the reported incidence in younger groups and from the Hardy-Weinberg equilibrium. This discrepancy appeared to be smaller in subjects of Mediterranean origin than in those of British or Irish genetic background.     

Allele frequencies of alpha-1-antitrypsin (PI) in the Balkans

The phenotype and allele frequencies of alpha-1-antitrypsin has been studied by an IEF technique (pH 4.2-4.9) in ten population samples from the Balkans. The allele frequencies varied from 0.6667 to 0.7361 (*M1), 0.1100 to 0.1793 (*M2), 0.0992 to 0.1700 (*M3), 0 to 0.0105 (*S), 0 to 0.0078 (*Z) and 0 to 0.0172 (others). The results were compared with data from South and Middle European populations from the literature. Most of the populations form a cluster with small genetic distances, and a weak relationship to geographical distributions. In contrast, the samples from Southern France, the Iberian Peninsula and Madeira form a clearly separated cluster. The differences are mainly based on high frequencies of PI*S in the latter populations.     

Porcine alpha-1-antitrypsin (PI): cDNA sequence, polymorphism and assignment to chromosome 7q2.4- > q2.6

A cDNA clone encoding the complete coding sequence for porcine alpha-1-antitrypsin (or α₁-protease inhibitor, PI) was isolated and its DNA sequence determined. The cDNA is assumed to encode alpha-1-antitrypsin on the basis of its sequence similarity to the corresponding cDNAs for human, baboon, rat, mouse, sheep and cow. The porcine cDNA clone was used in conjunction with BamHI, KpnI, MspI, SacI, TuqI and XbaI to develop restriction fragment length polymorphism-based genetic markers for linkage mapping in pigs. The cDNA has also been used to map the porcine PI locus to chromosome 7q2.4- > q2.6 by radioactive in situ hybridization. Thus, the PI locus has been added to the developing physical and genetic maps of the porcine genome.     

A newHLA-DRB1 * 13 allele (DRB1 * 1318) with a shortDRB1*08 sequence

The nucleotide sequence data reported in this paper have been submitted to the EMBL/GenBank nucleotide sequence database and have been assigned the accession number Z48631. The name listed for this sequence was officially assigned by the WHO Nomenclature Committee in November 1994. This follows the agreed policy that, subject to the conditions stated in the most recent Nomenclature Report (Bodmer et al. 1994), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO Nomenclature Report     

Alpha 1-antitrypsin Null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons.

alpha 1-Antitrypsin (alpha 1AT) deficiency, a common hereditary disorder responsible for emphysema in Caucasians of northern European descent, is caused by single base substitutions, deletions, or additions in the seven exons (IA-IC and II-V), of the 12.2-kb alpha 1AT gene located on chromosome 14 at q31-32.3. Of the five known representatives of the "null" group of alpha 1AT-deficiency alleles (alpha 1AT genes incapable of producing alpha 1AT protein detectable in serum) evaluated at the gene level, all result from mutations causing the formation of stop codons in coding exons of the alpha 1AT gene. The present study identifies an alpha 1AT allele (referred to as "Null(isola di procida")) caused by complete deletion of the alpha 1AT coding exons. The Null(isola di procida) allele was identified in an individual with heterozygous inheritance of M(procida) (an allele associated with alpha 1AT deficiency) and a null allele. Although results of karyotypic analysis were normal, quantification of the copies of alpha 1AT genes in this individual revealed that the index case had only half the normal copies of alpha 1AT genes. Cloning and mapping of the Null(isola di procida) gene demonstrated a deletion of a 17-kb fragment that included exons II-V of the alpha 1AT structural gene. As a consequence of the deletion, the normal noncoding exons (IA-IC) were followed by exons II-V of the downstream alpha 1AT-like gene. Sequence analysis of the deletion demonstrated a 7-bp repeat sequence (GAGGACA) both 5' to the deletion and at the 3' end of the deletion, a 4-bp palindromic sequence (ACAG vs. CTGT) bracketing the deletion, and a novel inserted 4-bp sequence (CCTG) at the breakpoint, suggesting that the mechanism of the deletion may have been "slipped mispairing."     

Chromosomal localization of the human alpha 1-antitrypsin gene (PI) to 14q31-32.

In situ hybridization of a recombinant cDNA probe containing the human alpha 1-antitrypsin gene to metaphase chromosomes demonstrated significant hybridization to chromosomal segment 14q31-32. A high percentage of cells analyzed (31%) displayed labeling on chromosome 14. Of all labeled sites on chromosome 14, 60% were found on segment 14q31-32. These results refine the previous assignment of the human alpha 1-antitrypsin gene to segment 14q24.1-32.1.     

Alpha-1-antitrypsin phenotypes in newborns from Central and Southern Italy.

The results of Pi typing on 500 infants from Central and Southern Italy are reported. Phenotype determinations were performed on umbilical cord serum. We observed nine different phenotypes; each of these is present in other European populations. The frequencies of the Pi alleles in our group were found to be, on the whole, comparable to those found in other populations widely separated geographically. However, the frequency of the Pi S gene in our sample (0.0670) was greater than that observed in Northern and Central European and American groups. Our Pi S frequency was similar to that found in a French group and lower than that of Spanish and Portuguese groups. Our data thus confirm the higher Pi S gene frequency in Latin populations.     

Alpha-1-antitrypsin and transferrin null alleles in the Portuguese population

In a Portuguese family, a null allele was found in the Pi system. An apparent 'exclusion' of the mother was found to be due to the presence of null alleles in mother and child. A transferrin (Tf) null allele was found in a case of disputed paternity. The mother and putative father were heterozygous for Tf null alleles and the child was homozygous (TfQ0) and presented hypotransferrinemia.     

Alpha-1 antitrypsin gene polymorphism in Chronic Obstructive Pulmonary Disease (COPD)

Alpha-1-antitrypsin (AAT) plays an important role in the pathogenesis of emphysema, the pathological lesion underlying the majority of the manifestations of Chronic Obstructive Pulmonary Disease (COPD). In this study we tested the hypothesis that common AAT polymorphisms influence the risk of developing COPDs. We investigated PiM1 (Ala213Val), PiM2 (Arg101His), PiM3 (Glu376Asp), PiS (Glu264Val) and PiZ (Glu342Lys) SERPINA1 alleles in 100 COPD patients and 200 healthy controls. No significant differences were observed in allele frequencies between COPD patients and controls, neither did haplotype analysis show significant differences between the two groups. A cross-sectional study revealed no significant relationship between common SERPINA1 polymorphisms (PiM1, PiM2, PiM3) and the emphysematous type of COPD. In addition, FEV(1) annual decline, determined during a two-year follow up period, revealed no difference among carriers of the tested polymorphisms.     

Another family with a silent allele of properdin factor B polymorphism (BF*QO)

Summary In five of eight members of a three generation family the existence of a silent allele of the properdin factor B polymorphism (BF^*QO) was indicated by immunofixation of BF electrophoretic variants and by the hemolytic overlay after isoelectric focusing of BF allotypes. This was further supported by the results of HLA-A, B, C, DR, C2, C4A, C4B, GLO-typing. BF protein was decreased in all heterozygous BF deficient family members. The absolute hemolytic activity, however, was obviously compensated for by an increased relative functional activity of the normal S or F alleles on the other chromosome.