AN IVS1-116 (A-]G) ACCEPTOR SPLICE-SITE MUTATION IN THE ALPHA(2) GLOBIN GENE CAUSING ALPHA(+) THALASSEMIA IN 2 DUTCH FAMILIES

We report the characterization of an alpha(+)- thalassaemia determinan t due to a transition A --> G of the acceptor splice consensus site se quence (IVS1-116) of the first intron of the alpha(2)-globin gene. The mutation, found in two apparently unrelated Dutch Caucasian families, was detected by DGGE analysis followed by direct sequencing. Haplotyp e analysis suggests a common origin of the mutation in both families. The disruption of the acceptor splice site consensus sequence interfer es with the correct splicing and leads to the retention of the first i ntron in the abnormally spliced mRNA. The alpha(+)-thalassaemia phenot ype observed in the carriers is caused by the absence of functional mR NA which cannot be replaced by the abnormally spliced mRNA. The low am ounts of abnormal mRNA found in reticulocytes is, most probably, due t o the post-transcriptional instability which follows the presence of a termination codon in the retained intronic sequence. This situation i s often associated with a decreased mRNA stability as observed for sev eral nonsense mutations of the beta-globin gene.