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

Abstract

The mtDNA variation of 50 Spanish and 4 Cuban families affected by nonsyndromic 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 population controls revealed that the A1555G mutation can be attributed to >/=30 independent mutational events among the 50 Spanish families and that it occurs on mtDNA haplogroups that are common in all European populations. This indicates that the relatively high detection rate of this mutation in Spain is not due to sampling biases or to a single major founder event. Moreover, the distribution of these mutational events on different haplogroups is compatible with a random occurrence of the A1555G mutation and tends to support the conclusion that mtDNA backgrounds do not play a significant role in the expression of the mutation. Overall, these findings appear to indicate that the rare detection of this mutation in other populations is most likely due to inadequacy in patient ascertainment and molecular screening. This probable lack of identification of the A1555G mutation in subjects affected by sensorineural hearing loss implies that their maternally related relatives are not benefiting from presymptomatic detection and information concerning their increased risk of ototoxicity due to aminoglycoside treatments.

Figure 1

Phylogenetic tree of RFLP haplotypes from patients with the deafness mutation A1555G. This mid-rooting-point maximum-parsimony tree includes 24 RFLP haplotypes (1–15 and 17–25) observed in 50 apparently unrelated Spanish patients (blackened circles), 2 RFLP haplotypes (16 and 26) observed in 4 Cuban patients (blackened squares), and the haplotypes previously described in 237 unrelated European controls. The capital letters H–M and T–X indicate haplogroups, and the numbers associated with the lowercase letters indicate the sites for restriction enzymes that define the specific haplogroups. The restriction enzymes are designated by single-letter code as follows: a = AluI; b = AvaII; c = DdeI; e = HaeIII; f = HhaI; g = HinfI; h = HpaI; k = RsaI; j = MboI; i = MspI; l = TaqI; m = BamHI; n = HaeII; q = NlaIII; r = BfaI; s = AccI; t = BstoI; u = MseI. The horizontal branch lengths are proportional to the number of mutational events that separate the haplotypes, with the exception of sites 10394c, 16303k, 16310k, and 16517e. In the parsimony analysis, these sites were assigned half the weight (i.e., 1) assigned to all other sites (i.e., 2). This tree is 430 steps in length and has consistency and retention indices of .652 and .896, respectively.