Aldur W. Eriksson

Molecular heterogeneity of steroid sulfatase deficiency: A multicenter study on 57 unrelated patients, at DNA and protein levels

Steroid sulfatase (STS) deficiency is the biochemical defect of X-linked ichthyosis (XLI), one of the most common X-linked disorders. We studied 57 European unrelated patients affected by STS deficiency. Twenty-eight patients were from Italy, 24 from the United Kingdom, 4 from The Netherlands, and 1 from Denmark. In two families XLI was associated with Kallmann syndrome (hypogonadotropic hypogonadism and anosmia). STS enzymatic activity was profoundly deficient in all cases. Direct DNA analysis, using cDNA and genomic probes from the STS gene and linked regions, demonstrated heterogeneity of the molecular defect. Forty-eight patients (84%) showed a deletion of the STS gene. In 44 cases the deletion also involved the STS flanking locus DXS237. In 1 patient a partial deletion of the STS gene was detected and in 9 patients no evidence of deletion was found. Locus DXS31 (probe M1A), previously mapped to Xp22.3-pter, was not deleted either in 24 patients with X-linked ichthyosis or in two families with X-linked ichthyosis associated with Kallmann syndrome. Consequently, the following loci order could be suggested: telomere--DXS31--(DXS237, STS)--Kallmann--centromere. Immunoblotting experiments, performed using anti-STS polyclonal antibodies, revealed the absence of cross-reacting material to STS in all cases tested, including 4 patients without evidence of deletions.

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.

Gene Mapping in Isolated Populations: New Roles for Old Friends?

Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from ‘New Finland’ and ‘Old Finland’ do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Åland Islands, Finland, and a collection of outbred Centre d’Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.

Weinberg's Differential Rule Reconsidered

ABSTRACT A central problem in research on twins is the estimation of the rates of monozygotic and dizygotic twin maternities. The estimation usually follows Weinbergs differential rule. According to this rule, the rate of dizygotic twinning is twice the rate of twin maternities in which the twins are of opposite sex. The monozygotic twinning rate is the difference between the rates of same-sex and opposite-sex twin sets. Weinbergs differential rule is implicitly based on the assumptions that the probability of a male equals the probability of a female and that the sexes in a dizygotic twin set are independent. Although Weinbergs differential rule has been the target of continuing discussions, the reliability of these assumptions has never been conclusively verified or rejected. In this study we present new variance formulas for the monozygotic and dizygotic twinning rates obtained using Weinbergs differential rule and stress that these new formulas have to be used. We analyze the accuracy of Weinbergs differential rule by considering alternative attempts. Especially, we build a general likelihood function and show that the maximum-likelihood estimates differ only slightly from the rates obtained using Weinbergs differential rule. In addition, our methods are applied to twinning data from Finland and Sweden. We compare our results with findings in the literature. In conclusion, our findings indicate that Weinbergs differential rule is rather robust and that despite its simplicity, it gives reliable results when official birth registers are analyzed.

Association of LOXL1 gene with Finnish exfoliation syndrome patients

In this study, three single-nucleotide polymorphisms (SNPs) on the lysyl oxidase-like 1 (LOXL1) gene associated with exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) were investigated in the Finnish population. A case–control study of 59 sporadic patients with XFS, 82 with XFG, 71 with primary open-angle glaucoma (POAG) and 26 individuals without these disorders from the southern Finnish population, and a family study of an extended family with 28 patients with XFS or XFG and 92 unaffected relatives from Kökar islands, Southwestern Finnish archipelago, were conducted. Anonymous blood donors (n=404) were studied as population-based controls. Three SNPs, rs1048661 (R141L), rs3825942 (G153D) and rs2165241, of the LOXL1 gene were genotyped by PCR sequencing. Association and linkage analyses were carried out. In both case–control and family materials, significant association for allele G of rs1048661 (P=2.65 × 10−5; P=0.0007), allele G of rs3825942 (P=2.24 × 10−8; P=0.49) and allele T of rs2165241 (P=2.62 × 10−13; P<0.0001) was found in XFS/XFG. However, linkage was not observed for LOXL1 risk alleles. The corresponding three-locus haplotype GGT increased the risk of XFS/ XFG nearly 15-fold relative to low-risk haplotype GAC (odds ratio (OR): 14.9, P=1.6 × 10−16). In conclusion, the earlier reported polymorphisms of the LOXL1 gene showed significant association also in the Finnish population.

Cytogenetic toxicity of antitumor platinum compounds in Fanconi's anemia

SummaryPeripheral blood lymphocytes of patients with Fanconis anemia (FA) were tested for their susceptibility to chromosome breakage by cis-platinum(II)-diamminedichloride [cis-Pt(II)], cis-platinum(IV)diamminetetrachloride [cis-Pt(IV)], and trans-platinum(IV)diamminetetrachloride [trans-Pt(IV)]. Low doses (0.1 μg/ml) of the DNA-DNA cross-linking agents cis-Pt(II) and cis-Pt(IV) dramatically increased the chromosome breakage level in FA cultures without affecting the controls. The predominantly DNA-protein cross-linking compound trans-Pt(IV), however, was much less effective in producing chromosomal damage in FA. The differential response of FA cells to cis-Pt(IV) and trans-Pt(IV) suggests that the high susceptibility of FA to bifunctional cross-linking agents is due to an impairment of the cells to tolerate DNA-DNA cross-links, rather than DNA-protein cross-links.

Demographic Analysis of the Variation in the Rates of Multiple Maternities in Sweden Since 1751

To elucidate the causes and mechanisms of twinning and higher multifetal maternities, we have taken advantage of the statistical sources of Sweden, where continuous statistics for the whole population are the oldest available. We found strong secular and regional fluctuations. The rates of multiple maternities were the highest during the last three decades of the 18th century, when the twinning rate was more than 17 per 1,000, the triplet rate was more than 3 per 10,000, and the quadruplet rate was almost 7 per 1 million maternities. During 1849-1873 the twinning rate in Sweden was 14.2 per 1,000, but this rate showed great regional differences, being 18.0 per 1,000 on the island of Gotland and 12.6 per 1,000 in the county of Älvsborg. During this period the twinning rate in the countryside in the county of Stockholm was 20.4, but in the city of Stockholm it was only 14.1 per 1,000. In Sweden after the 1930s there was a marked decrease in the twinning rate, which by the 1960s had fallen to only about half of what it had been two centuries earlier. The corresponding reductions for triplet and quadruplet rates were about 75%. The aim of this paper was to study the temporal and regional variations in multiple maternities in Sweden from 1751 to 1960 based on demographic and some socioeconomic data for the counties. We confirmed our earlier studies that maternal age and parity cannot satisfactorily explain the secular and regional differences in the twinning rates. In contrast to studies in France (1901-1968), we found no unequivocal association between the twinning rates and the crude birth rates. The correlation coefficients between the twinning rate and the crude birth rate showed statistically significant regional and temporal variations. After eliminating the temporal trends, regional differences in the correlation coefficients remained. The twinning rates for the counties seem to converge toward a common low level, 10-12 per 1,000. The observed convergence toward relatively similar levels may be caused by the increased matrimonial migration distances and decreased endogamy of the citizens as a consequence of better communications. The increased urbanization and industrialization that started in the last decades of the 19th century broke up the old static agrarian isolates and caused Sweden, within 2-3 generations, to develop from a poor nation to one of the most prosperous in the world. A more urban and affluent lifestyle, a better diet, and increased stress and sedentary occupations may have reduced the physical capacity of mothers to carry gestations with multiple embryos or fetuses to completion.

Genetic Background of Acute Anterior Uveitis

To determine the hereditary pattern of acute anterior uveitis, we examined seven families-one family with four cases, one family with three cases, and four families with two cases of acute anterior uveitis. A total of 16 patients with uveitis and 28 relatives underwent ocular examinations and serologic determination of HLA antigens, protease inhibitor alpha 1-antitrypsin typing, and X-ray examination of sacroiliac joints. Sacroiliitis was found in 11 of 16 patients (68.8%) and incomplete Reiters disease in seven of 16 (43.8%). HLA-B27 antigen was found in all patients with uveitis and in six of 21 (28.6%) relatives. HLA-Cw1 antigen was found in nine of 14 (64.3%) patients with uveitis, often in the same haplotype with HLA-B27 antigen. HLA-DR4 antigen was found in seven of 11 (63.6%) patients with uveitis. There was no significant association of the alpha 1-antitrypsin variant MZ with uveitis. We believe that a pleiotropic gene associated with HLA-B27 antigen with autosomal dominant inheritance, incomplete penetrance, and variable expressivity may determine susceptibility to acute anterior uveitis in linkage disequilibrium with HLA-Cwl antigen.

Historical epidemiology of smallpox in Åland, Finland: 1751–1890

We analyze a 140-year series of smallpox deaths in the Åland Islands, Finland. Vaccination, introduced in 1805, dramatically reduced the annual number of smallpox deaths. It also influenced the age distribution of smallpox deaths, changing smallpox from a childhood disease before 1805 to one which affected both adults and children after 1805. This appears to be due to the fact that Ålanders were usually vaccinated only once during childhood and often lost their immunity during adulthood. Spectral analysis of the prevaccination time series of smallpox deaths demonstrates a strong seven-year periodicity, reflecting the amount of time necessary to build up a cohort of nonimmune individuals. After the introduction of vaccination, the periodicity changes to eight years. The probability that a parish in Åland was affected by a smallpox epidemic is shown to be highly correlated with migration patterns and parish population sizes.

Stillbirth rates in singletons, twins and triplets in Sweden, 1869 to 2001.

The temporal variation in the stillbirth rates (SBR), measured as the number of stillborn per 1000 total births, among singletons, twins and triplets was studied on Swedish birth data for the period 1869 to 2001 and comparisons with data from other populations were made. Among both single and multiple births there were marked, almost monotonously decreasing trends in the stillbirth rates. Among singletons the stillbirth rate decreased from 29.5 per 1000 in the period 1869 to 1878 to 3.4 in the period 1991 to 2001. Among twins the stillbirth rate decreased from 94 per 1000 in 1869 to 1878 to a minimum of 8.2 in 1991 to 2001 and among triplets from 166 per 1000 to a minimum of 19.8. The relative declining pattern in the SBRs was almost the same, being 88% among singletons, 91% among twins and 88% among triplets. In the 1980s and 1990s the definition of the stillbirth rate was changed in many countries, including Finland, but no changes in the definition of stillbirths have been made in Sweden. The effect of the artificial reproduction techniques, including in vitro fertilization, on the rates of multiple maternities is also discussed. It was noted especially that they had a more marked effect on the triplet than on the twinning rate.