The A1555G mutation in the 12S rRNA gene of human mtDNA: Recurrent originsand founder events in families affected by sensorineural deafness

The mtDNA variation of 50 Spanish and 4 Cuban families affected by nonsyndr omic sensorineural deafness due to the A1555G mutation in the 12S rRNA gene was studied by high-resolution RFLP analysis and sequencing of the control region. Phylogenetic analyses of haplotypes and detailed survey of populat ion controls revealed that the A1555G mutation can be attributed to greater than or equal to 30 independent mutational events among the 50 Spanish fam ilies and that it occurs on mtDNA haplogroups that are common in all Europe an populations. This indicates that the relatively high detection rate of t his mutation in Spain is not due to sampling biases or to a single major fo under event. Moreover, the distribution of these mutational events on diffe rent haplogroups is compatible with a random occurrence of the A1555G mutat ion and tends to support the conclusion that mtDNA backgrounds do not play a significant role in the expression of the mutation. Overall, these findin gs appear to indicate that the rare detection of this mutation in other pop ulations is most likely due to inadequacy in patient ascertainment and mole cular screening. This probable lack of identification of the A1555G mutatio n in subjects affected by sensorineural hearing loss implies that their mat ernally related relatives are not benefiting from presymptomatic detection and information concerning their increased risk of ototoxicity due to amino glycoside treatments.