VARIANTS OF THE MOLECULAR CHAPERONE HSPA8 AND HSPA1A GENES IN TRIMETHYLAMINURIA: A PILOT STUDY

There is discrepancy in the phenotypic manifestations of trimethylaminuria (TMAU) between
patients suggesting a certain diversity of etiological-pathogenic factors. Primary TMAU is linked to
mutations in the FMO3 gene but a proportion of patients do not carry mutations in it or carry single
nucleotide polymorphisms (SNPs) that do not have an impact on the gene’s product, the enzyme
FMO3. It remains to be established what other factors are pathogenic in TMAU underpinning the
various phenotypes. We hypothesized that defective chaperones could contribute to the
pathogenesis by, for example, failing to assist FMO3 in its folding and refolding cycles. In the
initial screening reported here we investigated two chaperone genes, HSPA8 and HSPA1A in
twelve TMAU patients and found that variants in the former were highly represented in comparison
with controls. Further studies, including more patients are underway to firmly establish the
prevalence of the variants and to begin elucidating molecular mechanisms.