| Summary: | 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/K) 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. © 2009 Elsevier Inc. All rights reserved.
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