Congenital afibrinogenemia: mutations leading to premature termination codons in fibrinogen AO-chain gene are not associated with the decay of the mutant mRNAs

Congenital afibrinogenemia is a rare coagulation disorder with autosomal recessive inheritance, characterized by the complete absence or extremely reduced levels of fibrinogen in patients, plasma and platlets. Eight afibrinogemic probands, with very low plasma levels of immunoreactive fibriogen were studied. Sequencing of the fibrinogen gene cluster of each proband disclosed 4 novel point mutations (1914C>G, 1193G> T, 1215delT, and 3075C> T) and 1 already reported (3192C>T). All mutations, localized within the first 4 exons of the AO-chain gene, were null mutations predicted to produce severely truncated AO-chains because of the presence of premature termination codons. Since premature termination codons are frequently known to affect the metabolism of the corresponding messenger RNAs (mRNAs), the degree of stability of each mutant mRNA was investigated. Contransfection experiments with plasmids expressing the wild type and each of the mutant AO-chains, followed by RNA extraction and semiquantative reversetranscriptase-polymerase chain reaction analysis, demonstrated that all the identified null mutations escaped nonsense-mediated mRNA decay. Moreover, ex vivo analysis at the protein level demonstrated that the presence of each mutation was sufficient to abolish fibrinogen sectretion. (AU)

The epidemiology and service implications of congenital and constitutional anomalies in ethnic minorities in the United Kingdom

The literature on the incidence in the UK of congenital and constitutional anomalies in populations deriving from Africa, the Caribbean, the Far East, the Indian subcontinent and the Mediterranean is reviewed. These groups represent an increasing proportion of the whole child population. Comparison with the white population and between groups reveals that the burden of impairment varies with country of origin. Some of the reasons implicated include different gene frequencies and mating patterns, age/parity distribution and uptake of preventive services. Comparisons with prevalence at birth in the countries of origin are made where possible. In general, populations with high rates in their country of origin retain their high rates (e.g. central nervous system anomalies among births to parents deriving from the Indian subcontinent). There is a general lack of data on the prevalence of handicapping conditions such as cerebral palsy, as well as the associated health needs and service utilisation amongst ethnic minorities. (AU)