A FREQUENT TG DELETION NEAR THE POLYADENYLATION SIGNAL OF THE HUMAN HEXB GENE - OCCURRENCE OF AN IRREGULAR DNA-STRUCTURE AND CONSERVED NUCLEOTIDE-SEQUENCE MOTIF IN THE 3'-UNTRANSLATED REGION

While screening for new mutations in the HEXB gene, which encodes the beta-subunit of beta-hexosaminidase, a TG deletion (Delta TG) was foun d in the 3' untranslated region (3'UTR) of the gene, 7 bp upstream fro m the polyadenylation signal. Examination of DNA samples of 145 unrela ted Argentinean individuals from different racial background showed th at the Delta TG allele was present with a frequency of approximately 0 .1, compared with the wild-type (WT) allele. The deletion was not asso ciated with infantile or variant forms of Sandhoff disease when presen t in combination with a deleterious allele. Total Hex and Hex B enzyma tic activities measured in individuals heterozygous for Delta TG and a null allele, IVS-2 + 1G --> A (G --> A), were approximately 30% lower than the activities of G --> A/WT individuals, Analysis of the HEXB m RNA from leukocytes of Delta TG/WT WT individuals by RT PCR of the 3'U TR showed that the Delta TG allele is present at lower level than the WT allele, By polyacrylamide gel electrophoresis, it was determined th at a PCR fragment containing the +TG version of the 3'UTR of the HEXB gene had an irregular structure.On inspection of genes containing a TG dinucleotide upstream from the polyadenylation signal we found that t his dinucleotide was part of a conserved sequence (TGTTTT) immersed in a A/T-rich region. This sequence arrangement was present in more than 40% analyzed eukaryotic mRNAs, including in the human, mouse and cat HEXB genes, The significance of the TG deletion in reference to Sandho ff disease as well as the possible functional role of the consensus se quence and the DNA structure of the 3'UTR are considered. Hum Mutat 12 :320-329, 1998. (C) 1998 Wiley-Liss, Inc.