Pre-eclampsia is a disorder of human pregnancy occurring in 5-10% of all births, and represents the leading cause of infant morbidity and mortality and maternal death. In pre-eclampsia, invasion of fetal trophoblasts into maternal arteries during early pregnancy is shallow or absent. Here we examined the hypothesis that HLA-G, a non-classical class I HLA expressed in cytotrophoblasts, may act as a key gene in pre-eclampsia. We analysed HLA-G at the level of transcription and genotyped a silent CAC-CAT polymorphism in exon 3 and a 14-bp insertion/deletion in the 3' untranslated region. A deficit in levels of the HLA-G3 transcript was observed in mild pre-eclampsia compared to normal placentas. The distribution of HLA-G polymorphisms was different between normal and pre-eclampsia samples. A correlation between the alteration in transcription of the HLA-G gene and certain HLA-G genotypes was also observed. Thus we provide the first evidence for a possible role of HLA-G in genetic susceptibility to, and pathogenesis of pre-eclampsia.

Malignant hyperthermia (MH) is a potentially life-threatening event in response to anesthetic triggering agents, with symptoms of sustained uncontrolled skeletal muscle calcium homeostasis resulting in organ and systemic failure. Susceptibility to MH, an autosomal dominant trait, may be associated with congenital myopathies, but in the majority of the cases, no clinical signs of disease are visible outside of anesthesia. For diagnosis, a functional test on skeletal muscle biopsy, the in vitro contracture test (IVCT), is performed. Over 50% of the families show linkage of the IVCT phenotype to the gene encoding the skeletal muscle ryanodine receptor and over 20 mutations therein have been described. At least five other loci have been defined implicating greater genetic heterogeneity than previously assumed, but so far only one further gene encoding the main subunit of the voltage-gated dihydropyridine receptor has a confirmed role in MH. As a result of extensive research on the mechanisms of excitation-contraction coupling and recent functional characterization of several disease-causing mutations in heterologous expression systems, much is known today about the molecular etiology of MH.

To whom reprint requests should be sent Communicated by T. LindahlThe three miscoding alkylated pyrimidines 02-methylcytosine, 02-methylthymine and 04-methylthymine are specifically recognized by Escherichia coli DNA repair enzymes. The activities are induced as part of the adaptive response to alkylating agents. 02-Methylcytosine and O2_ methylthymine are removed by a DNA glycosylase, the alkA + gene product, which also acts on N3-methylated purines. 04-Methylthymine is repaired by a methyltransferase, previously known to correct 06-methylguanine by transfer of the methyl group to one of its own cysteine residues. It is proposed that certain common structural features of the various methylated bases allow each of the two inducible repair enzymes to recognize and remove several different kinds of lesions from alkylated DNA.

Malignant hyperthermia (MH) is a potentially fatal pharmacogenetic disease triggered by several anaesthetic agents. The in vitro muscle contracture test (IVCT) is the standard test to establish an individual's risk of susceptibility to MH. Clinical practitioners and geneticists of the European MH Group have agreed on the present guidelines for the detection of MH susceptibility using molecular genetic techniques and/or IVCT to predict the risk of MH.

Pre-eclampsia (PE) is uniquely a disease of pregnancy and is the major cause of foetal and maternal morbidity and mortality. Epidemiological studies show that PE is highly heritable, with a high incidence in all populations. The underlying pathology indicates that absent or shallow invasion of foetal trophoblasts into maternal arteries is a feature of true PE. The objective of this study was to determine the genetic factors influencing PE. A large number of mother-father-baby trios were collected in which the first pregnancy was complicated by severe PE. After careful examination of the epidemiology and pathology of the disease, two plausible candidate genes, namely insulin-like growth factor II (IGF-II) and HLA-G, were analysed for association with PE. No association was found between a commonly occurring polymorphism in IGF-II and PE. Three polymorphisms in HLA-G were analysed in the sample cohorts. No association was found between three polymorphisms in HLA-G and PE. However, the frequency of the HLA-G insertion/deletion polymorphism in exon 8 deviated significantly from Hardy-Weinberg expectations in PE off-spring, reflecting an excess of heterozygotes for these polymorphisms in PE offspring. The significance of this deviation is not clear and further genetic analysis will be necessary to confirm this finding and to explore further the candidacy of HLA-G in PE.