Mitochondrial tRNA(Thr) G15927A mutation may modulate the phenotypic manifestation of otatoxic 12S rRNA A1555G mutation in four Chinese families

Objective To investigate the role of mitochondrial modifiers in the development of deafness associated with 12S rRNA A1555G mutation. Methods Four Chinese families with nonsyndromic and aminoglycoside-induced deafness were studied by clinical and genetic evaluation, molecular and biochemical analyses of mitochondrial DNA (mtDNA). Results These families exhibited high penetrance and expressivity of hearing impairment. Penetrances of hearing loss in WZD31, WZD32, WZD33, and WZD34 pedigrees ranged from 50 to 67% and from 39 to 50%, respectively, when aminoglycoside-induced hearing loss was included or excluded. Matrilineal relatives in these families developed hearing loss at the average of 14,13,16, and 15 years of age, respectively, when aminoglycoside-induced deafness was excluded. Mutational analysis of entire mtDNA in these families showed the homoplasmic A1555G mutation and distinct sets of variants belonging to haplogroup B5bl. Of these, the tRNA(Thr) G15927A mutation locates at the fourth base in the anticodon stem (conventional position 42) of tRNA(Thr) A guanine (G42) at this position of tRNA:rh, is highly conserved from bacteria to human mitochondria. The lower levels and altered electrophoretic mobility of tRNA(Thr) were observed in cells carrying A1555G and G15927A mutations or only G15927A mutation but not cells carrying only A1555G mutation. The abolished base pairing (28C-42G) of this tRNA(Thr) by the G15927A mutation caused a failure in tRNA metabolism, worsening the mitochondrial dysfunctions altered by the A1555G mutation. Conclusion The G15927A mutation has a potential modifier role in increasing the penetrance and expressivity of the deafness-associated 12S rRNA A1555G mutation in those Chinese pedigrees. Pharmacogenetics and Genomics 18:1059-1070 (C) 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.