Beverly R. Akerman

Two novel mutations of the FMO3 gene in a proband with trimethylaminuria

The mammalian flavin‐containing monooxygenases catalyze the NADPH‐dependent N‐oxygenation of nucleophilic nitrogen‐, sulfur‐, and phosphorus‐containing chemicals, drugs, and xenobiotics, including trimethylamine. The FMO3 gene encodes the dominant catalytically active isoform present in human liver. We have identified two missense mutations in the coding region of the gene in a proband with trimethylaminuria (TMA): M66I and R492W. Whereas two mutations (P153L, E305X) accounted for TMA in our eight unrelated previously documented Australian families of British origin, the present report is the first evidence of compound heterozygosity for two rare mutations in a proband with this disorder. This suggests that other rarer alleles, also causing TMA, will be found in the same populations. Hum Mutat 13:376–379, 1999.

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 β‐subunit of β‐hexosaminidase, a TG deletion (ΔTG) was found in the 3′ untranslated region (3′UTR) of the gene, 7 bp upstream from the polyadenylation signal. Examination of DNA samples of 145 unrelated Argentinean individuals from different racial backgrounds showed that the ΔTG allele was present with a frequency of approximately 0.1, compared with the wild‐type (WT) allele. The deletion was not associated with infantile or variant forms of Sandhoff disease when present in combination with a deleterious allele. Total Hex and Hex B enzymatic activities measured in individuals heterozygous for ΔTG 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 mRNA from leukocytes of ΔTG/WT individuals by RT‐PCR of the 3′UTR showed that the ΔTG allele is present at lower level than the WT allele. By polyacrylamide gel electrophoresis, it was determined that 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 this 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 Sandhoff disease as well as the possible functional role of the consensus sequence and the DNA structure of the 3′UTR are considered. Hum Mutat 12:320–329, 1998.© 1998 Wiley‐Liss, Inc.