Loss-of-function mutations in the
flavin-containing monooxygenase 3 gene (
FMO3) cause the inherited disorder
trimethylaminuria (
TMAuria), or fish-odour syndrome. Here we describe the identification in a family from northern Norway of a novel causative mutation of
TMAuria. A female child within the family presented with a
TMAuria-like phenotype. The child and her mother were found to be heterozygous for a novel mutation (R238Q) in exon 6 of
FMO3. The child's father lacked this mutation, but was heterozygous for a double polymorphic variant, E158K/E308G, which was not present in the child. During a consultation with her doctor the mother mentioned an uncle whom she remembered as having a strong body odour. This discussion led to genetic counselling of the uncle and analysis of his
DNA showed him to be homozygous for the R238Q mutation. Analysis of the mutant
FMO3 expressed in bacteria revealed that the R238Q mutation abolished catalytic activity of the
enzyme and is thus a causative mutation for
TMAuria. The specificity constant (k(cat)/K(M)) of the K158/G308 variant was 43% of that of ancestral
FMO3. Because the child is heterozygous for the R238Q mutation and no other mutation known to cause
TMAuria was detected in her
DNA she is predicted to suffer from transient childhood
TMAuria, whereas her great-uncle has primary
TMAuria.