title: Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation.
abstract: Mitochondrial 12S rRNA 1555A>G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic deafness. Our previous investigations showed that the A1555G mutation was a primary factor underlying the development of deafness but was insufficient to produce deafness phenotype. However, it has been proposed that mitochondrial haplotypes modulate the phenotypic manifestation of the 1555A>G mutation. Here, we performed systematic and extended mutational screening of 12S rRNA gene in a cohort of 1742 hearing-impaired Han Chinese pediatric subjects from Zhejiang Province, China. Among these, 69 subjects with aminoglycoside-induced and nonsyndromic deafness harbored the homoplasmic 1555A>G mutation. These translated to a frequency of approximately 3.96% for the 1555A>G mutation in this hearing-impaired population. Clinical and genetic characterizations of 69 Chinese families carrying the 1555A>G mutation exhibited a wide range of penetrance and expressivity of hearing impairment. The average penetrances of deafness were 29.5% and 17.6%, respectively, when aminoglycoside-induced hearing loss was included or excluded. Furthermore, the average age-of-onset for deafness without aminoglycoside exposure ranged from 5 and 30years old, with the average of 14.5years. Their mitochondrial genomes exhibited distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups A, B, C, D, F, G, M, N, R and Y, respectively. These indicated that the 1555A>G mutation occurred through recurrent origins and founder events. The haplogroup D accounted for 40.6% of the patient's mtDNA samples but only 25.8% of the Chinese control mtDNA samples. Strikingly, these Chinese families carrying mitochondrial haplogroup B exhibited higher penetrance and expressivity of hearing loss. In addition, the mitochondrial haplogroup specific variants: 15927G>A of haplogroup B5b, 12338T>C of haplogroup F2, 7444G>A of haplogroup B4, 5802T>C, 10454T>C, 12224C>T and 11696G>A of D4 haplogroup, 5821G>A of haplogroup C, 14693A>G of haplogroups Y2 and F, and 15908T>C of Y2 may enhance the penetrace of hearing loss in these Chinese families. Moreover, the absence of mutation in nuclear modifier gene TRMU suggested that TRMU may not be a modifier for the phenotypic expression of the 1555A>G mutation in these Chinese families. These observations suggested that mitochondrial haplotypes modulate the variable penetrance and expressivity of deafness among these Chinese families.
authors.affiliation: Zhejiang Provincial Key Laboratory of Medical Genetics and Attardi Institute of Mitochondrial Biomedicine, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Yaping
authors.initials: Y
authors.lastname: Qian
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Li
authors.forename: Aifen
authors.initials: A
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Tang
authors.forename: Bobei
authors.initials: B
authors.lastname: Chen
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Li
authors.forename: Junyan
authors.initials: J
authors.lastname: You
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Tao
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.forename: Jindan
authors.initials: J
authors.lastname: Wang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Sun
authors.forename: Jianyue
authors.initials: J
authors.lastname: Zhao
authors.forename: Yanzi
authors.initials: Y
authors.lastname: Meng
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000617:Aminoglycosides / Q000009:adverse effects; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002681:China; D004272:DNA, Mitochondrial / Q000235:genetics*; D003638:Deafness / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology*; D006239:Haplotypes / Q000235:genetics*; D034381:Hearing Loss / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008928:Mitochondria / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D010802:Phylogeny; D012335:RNA, Ribosomal / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S