Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation.
Mitochondrial haplotypes may modulate the phenotypic manifestation of the deafness-associated 12S rRNA 1555A>G mutation.
复制标题
DOI：
10.1016/j.mito.2009.09.007
复制
发表时间：
2010-01
期刊：
影响因子：
4.4
通讯作者：
Guan, Min-Xin
中科院分区：
文献类型：
--
作者：
Lu, Jianxin;Qian, Yaping;Li, Zhiyuan;Yang, Aifen;Zhu, Yi;Li, Ronghua;Yang, Li;Tang, Xiaowen;Chen, Bobei;Ding, Yu;Li, Yongyan;You, Junyan;Zheng, Jing;Tao, Zhihua;Zhao, Fuxin;Wang, Jindan;Sun, Dongmei;Zhao, Jianyue;Meng, Yanzi;Guan, Min-Xin
线粒体12S rRNA 1555A和GT；G突变是氨基糖苷类致聋和非综合征性耳聋的重要原因之一。我们以前的研究表明，A1555G突变是导致耳聋发生的主要因素，但不足以产生耳聋表型。然而，有人提出线粒体单倍型调节1555A和GT；G突变的表型表现。在本研究中，我们对浙江省1 742名汉族听障儿童中国的12SRRNA基因进行了系统和广泛的突变筛查。其中，69例氨基糖苷类诱导性耳聋和非综合征性耳聋患者携带1555A和GT；G突变。在这些听力受损人群中，1555A和GT；G突变的频率约为3.96%。69个携带1555A>；G突变的中国家系的临床和遗传特征显示出广泛的听力障碍的外显率和表达能力。当计入或排除氨基糖苷类药物所致听力损失时，平均听力损失分别为29.5%和17.6%。此外，未接触氨基糖苷类药物的耳聋患者的平均发病年龄为5岁至30岁，平均14.5岁。它们的线粒体基因组分别属于东亚10个单倍群A、B、C、D、F、G、M、N、R和Y。这表明1555A和GT；G突变是通过反复发生的起源和创始人事件发生的。D单倍型占患者mtDNA样本的40.6%，但仅占中国对照mtDNA样本的25.8%。值得注意的是，这些携带线粒体单倍群B的中国家庭表现出更高的外显率和听力损失的表现力。此外，线粒体单倍群特异变异：B5b单倍群15927G和GT；A、F2单倍群12338T>；C、B4单倍群7444G>；A、D4单倍群5802T>；C、D4单倍群12224C>；A、5821G>；C单倍群A、Y2和F单倍群A、14693A>；以及Y2的b可能增强了这些中国家系的听力损失。此外，核修饰基因TRMU没有突变，提示TRMU可能不是1555A>；G突变表型表达的修饰基因。这些观察表明，线粒体单倍型在这些中国家庭中调节了耳聋的变量外显性和表现性。
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 ~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 30 years old, with the average of 14.5 years. 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 b 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.
登录
查看更多内容
影响因子：
5.3
作者：
Guan, MX;Enriquez, JA;Attardi, G
通讯作者：
Attardi, G
影响因子：
5.2
作者：
Jacobs, HT;Hutchin, TP;Mueller, RF
通讯作者：
Mueller, RF
影响因子：
2
作者：
Chen, Bobei;Sun, Dongmei;Guan, Min-Xin
通讯作者：
Guan, Min-Xin
影响因子：
5.3
作者：
Li, ZY;Li, RH;Guan, MX
通讯作者：
Guan, MX
影响因子：
14.9
作者：
Li, XM;Fischel-Ghodsian, N;Guan, MX
通讯作者：
Guan, MX