线粒体tRNAThr G15927A突变可能影响耳聋相关的12S rRNA A1555G突变的表型表达

摘要: 对1个中国汉族耳聋家系进行了临床和分子遗传学特征分析。家系中听力下降的母系成员表现为程度不等、听力图形态不同的听力损害, 但同为双侧对称的感觉神经性耳聋。该家系耳聋外显率很高, 包括药物致聋的耳聋外显率为75%, 而非药物致聋的外显率为41.7%。对母系成员进行线粒体DNA(mtDNA)全序列扩增分析, 发现了耳聋相关12S rRNA A1555G同质性突变位点和多态性位点, 属于东亚人群B5b单体型。在这些变异位点中, mtDNA 15927位点的G-A碱基变化破坏tRNA^Thr反密码子结构上十分保守的C-G碱基对, 这可能加重由A1555G突变造成的线粒体功能缺陷。这表明tRNAThrG15927A突变可能增强携带12S rRNA A1555G的中国汉族耳聋家系的外显率和表现度。     

25个携带线粒体12S rRNA A1555G 突变的中国汉族非综合征型耳聋家系

线粒体12S rRNA A1555G突变是引起氨基糖甙类药物诱导的非综合征型耳聋的重要原因之一。文章对收集的25个携带A1555G突变的中国汉族非综合征型耳聋家系进行了临床和分子遗传学评估。结果表明,这25个家系的母系成员在耳聋外显率、听力损失严重程度和发病年龄上存在较大差异。当包括和不包括氨基糖甙类药物使用史时,耳聋的平均外显率分别为28.1%和21.5%,排除氨基糖甙类药物时,耳聋的平均发病年龄从1~15岁不等。线粒体全序列分析发现了16个新变异,不同的线粒体DNA多态性位点显示这25个家系分别属于东亚人群A、B、D、F、G、M、N和R单倍型,其中线粒体单倍型B的家系耳聋外显率和表现度较其他单倍型高。此外,7个继发突变位点和21个高保守性位点突变可能增加了这些家系的耳聋外显率。GJB2基因上未检测到与耳聋相关的突变,表明在本研究的耳聋家系中,GJB2基因可能没有参与A1555G突变的表型表达。以上各方面提示,线粒体单倍型和其他因素可能参与了这25个家系耳聋患者的表型修饰。     

携带线粒体tRNA~(Thr) 15943T>C协同12S rRNA 1555A>G突变的非综合征性耳聋致病机理的初步研究

该研究通过构建携带线粒体tRNA~(Thr )15943TC协同12S rRNA 1555AG突变(双突变组)的永生化淋巴母细胞系,同时建立仅含12S rRNA 1555AG突变(单突变组)和正常对照组永生化淋巴母细胞系,探究线粒体tRNA~(Thr )15943TC协同12S rRNA 1555AG突变与耳聋发病的关系,以了解线粒体突变致聋的分子机制。对该家系的临床资料进行分析的结果表明,当包括使用氨基糖苷类抗生素(aminoglycoside antibiotic,AmAn)的药物性耳聋家系成员时,此家系耳聋外显率为26%;当排除用药的耳聋成员时,此家系耳聋外显率是10%;相比之下,已报道的14个m.1555AG的耳聋家系的平均外显率在用药和未用药的情况下分别仅为13%和6%。利用Northern blot和Western blot分别检测三组细胞中线粒体tRNA和多肽的表达量,结果表明相比于正常对照组,tRNA~(Thr)在双突变组中的表达量显著降低,而在单突变组中的表达量无显著变化,tRNA~(Trp)、tRNA~(Ala) 、tRNA~(Tyr) 、tRNA~(Cys)和tRNA~(Pro)的稳态水平在三组细胞中没有显著性差异;CO2、CO3和A6在双突变组中的表达量显著降低,而在单突变组中的表达量无显著性差异;其他蛋白多肽在三组细胞中的表达量没有显著差异,说明m.15943TC突变降低了tRNA~(Thr)的稳态水平,致使线粒体部分多肽表达水平下降,从而影响了线粒体呼吸链复合体的功能和稳定性进而导致了线粒体代谢障碍,提示线粒体tRNA~(Thr) 15943TC可能与m.1555AG突变引起的耳聋相关。     

线粒体T12338C突变可能是与Leber遗传性视神经病变相关的突变位点

Leber遗传性视神经病变变(Leber’s hereditary optic neuropathy,LHON)是一种与线粒体DNA(Mito-chondrial DNA,mtDNA)突变相关的母系遗传性眼科疾病。文章报道了两例具有典型LHON临床、分子遗传特征的中国汉族家系。首先通过对家系先证者和其他成员进行眼科相关检查,发现两个家系成员中视力都仅有先证者一人损害严重,即外显率很低。经常规的方法对母系成员进行mtDNA测序及相关软件分析,结果发现携带ND4 G11696A和ND5 T12338C同质性突变位点,多态性变异位点均属于东亚单体型F2。线粒体DNA ND4 G11696A是一个已知的与LHON相关的突变位点,而T12338C位于线粒体氧化磷酸化复合体I亚基ND5的第2个碱基,该突变使起始密码子由蛋氨酸转变成苏氨酸,并且紧连tRNALeu(CUN)的3′末端。这可能影响tRNA Leu(CUN)空间结构和稳定性发生改变,以及起始密码子改变导致线粒体ND5蛋白合成功能受损和ATP障碍,最终导致需求能量高的视神经受损和视力损害。因此,线粒体ND4 G11696A和ND5 T12338C突变可能协同作用Leber遗传性视神经病变的发生,是与LHON相关的mtDNA突变位点,但外显率很低说明突变本身不足以造成LHON的表型表达,提示其他修饰因子(核修饰基因、环境等)可能对这两个家系发病起协同作用。     

人工耳蜗植入聋儿术前基因检测及家系分析

摘要: 国内外研究表明GJB2、SLC26A4(PDS)和线粒体DNA(Mitochondrial DNA, mtDNA)的病理性突变导致了大部分的遗传性聋。 文章收集了2006年4月~2007年9月接受人工耳蜗(Cochlear implant, CI)植入的14 例患儿及其父母的外周血, 应用基因诊断方法进行 GJB2、SLC26A4(PDS)和mtDNA 1555位点突变检测。结果显示, 35.7%的患儿检测到致病突变, 其中28.6%为GJB2基因突变, 类型均为235delC纯和突变, 其父母为携带GJB2 235delC的杂和子; 7.1%为mtDNA A1555G突变, 其母亲亦携带mtDNA A1555G突变。这表明CI 植入聋儿最常见的基因突变是GJB2 235delC突变, 其次是mtDNA A1555G突变, 通过对耳聋家系常见致病基因的检测和家系分析, 可以对优生优育及减少耳聋发病率提供科学准确的遗传信息。     

一个2型糖尿病家系中新发现的线粒体DNA G7444A 突变分析

应用PCR-RFLP和测序对一个2型糖尿病家系的线粒体DNA G7444A的突变进行检测, 并分析其临床资料的特点。结果发现, 27例家系成员中, 11例母系亲属均存在线粒体DNA G7444A突变, 而配偶及父系亲属中未发现该突变。11例突变者中确诊为2型糖尿病患者5例, 糖耐量受损1例, 均表现为乳酸和血糖增高。因此, 线粒体DNA G7444A突变是该家系中糖尿病的遗传易感因素, 是导致2型糖尿病的一个新的突变位点。     

携带线粒体tRNA~(Thr)15910C>T突变和12S rRNA 1555A>G突变的非综合征型耳聋家系的线粒体功能研究

该研究旨在探讨一个非综合征型耳聋(nonsyndromic hearing impairment,NSHI)家系中线粒体t RNAThr 15910CT和12S r RNA 1555AG基因突变共同作用对线粒体功能的影响。该研究建立了同时携带线粒体t RNAThr 15910CT和12S r RNA 1555AG基因突变(双突变组)、仅携带12S r RNA 1555AG基因突变(单突变组)和对照组的永生化淋巴细胞,这3组细胞系的线粒体DNA单体型均属于R单体型。对该家系的临床资料进行分析,当包括使用氨基糖苷类抗生素(aminoglycoside antibiotics,Am An)的药物性耳聋家系成员时,此家系耳聋外显率为37.5%;当排除用药的耳聋成员时,耳聋外显率是25.0%;相比之下,在用药和未用药的情况下,已报道的14个m.1555AG的耳聋家系的平均外显率只有12.8%和6.1%。通过对双突变组、单突变组和对照组永生化细胞系的线粒体功能进行研究,结果发现与对照组相比,双突变和单突变组细胞系的ROS水平分别上升了19.08%(P=0.005 4)和9.05%(P=0.003 7);ΔΨm水平分别下降了47.78%(P=0.006 3)和35.39%(P=0.0245);复合体II活力分别下降了8.26%(P=0.721 1)和19.48%(P=0.004 9),复合体IV活力分别下降了32.75%(P=0.033 5)和27.44%(P=0.180 5)。m.1555AG与m.15910CT共同作用,导致ROS生成量升高,ΔΨm水平下降以及线粒体呼吸链复合体IV活力降低等线粒体功能缺陷,提示m.15910CT可能是m.1555AG导致耳聋的继发性突变。     

一个母系遗传非综合征耳聋大家系mtDNA序列分析

通过分析本家mtDNA序列,探讨淮阴一非综合耳聋大家患病的分子遗传学机制。采用聚合酶链反应（PCR）扩增mtDNA与非综合征耳聋相关位点nt1555,nt7445的区域和人类种群研究的D－loop区,PCR－异源双链分析,PCR－RFLP、PCR产物克隆序列测定等技术对该家系进行了系统的研究。发现该家系中全部母系亲属有mtDNAA1555G突变,而家系中非母 个体,对照组（100例正常个体）的mtDNA1555位点均为A。该家系mtDNA7445位点无突变;该系属于Ⅱ型线性体;发现家系D－loop区存在未见报道的碱基插入。提示mtDNAA1555G位点突变可能是导致该家系患致聋的主要因素之一。遗传背景可能对家系疾病的表现存在一定程度的影响。     

核基因参与人类线粒体12S rRNA突变相关非综合征耳聋的临床表型

人类线粒体DNA 12S rRNA A1555G突变可引起母系遗传性非综合征耳聋,并提高氨基糖甙类药物对该类耳聋的诱导作用。我们在江苏淮阴发现了一个非综合征耳聋大家系,家系个体发病呈典型的母系遗传特征,临床可表现为先天性耳聋、中年进行性耳聋乃至完全正常的表型。对家系个体进行研究后发现A1555G突变是引起该家系耳聋的主要原因。我们用EB病毒转化的方法对该家系部分个体行建系工作后,对家系中17个个体的类淋巴母细胞进行分析,其中包括具有耳聋症状的个体7人(患者组),具有同质性A1555G突变但表型正常的个体6人(携带组),正常婚配对照 5人,与正常婚配对照相比,患者组与携带组在线粒体蛋白合成速率及在葡萄糖或半乳糖培养基中的生长速度出现了不同程度的下降,且突变细胞系中线粒体功能缺陷的严重程度与个体的临床表型相关．这些发现强有力地支持了核基因参与了该疾病临床表型的形成。     

一个母系遗传非综合征耳聋大家系mtDNA序列分析

通过分析本家系mtDNA序列,探讨淮阴一非综合征耳聋大家系患病的分子遗传学机制.采用聚合酶链反应(PCR)扩增mtDNA与非综合征耳聋相关位点nt1555、nt7445的区域和人类种群研究的D-loop区、PCR-异源双链分析、PCR-RFLP、PCR产物克隆序列测定等技术对该家系进行了系统的研究.发现该家系中全部母系亲属有mtDNAA1555G突变,而家系中非母系个体、对照组(100例正常个体)的mtDNA1555位点均为A.该家系mtDNA7445位点无突变;该家系属于II型线粒体;发现家系D-loop区存在未见报道的碱基插入.提示mtDNAA1555G位点突变可能是导致该家系患者致聋的主要因素之一.遗传背景可能对家系疾病的表型存在一定程度的影响。 Abstract:We find an extensive nonsyndromic sensorineural deafness family in Huaiyin,and investigate the possible molecular genetic mechanism of matrilineal nonsyndromic sensorineural deafness.We use PCR,combined with PCR-heteroduplex analysis,PCR-RFLP and sequencing techniques to examine part of 12S rRNA,tRNAser(UCN),and D-loop region of this pedigree.1)We found an A to G transition at position 1555(A1555G) of the mitochondrial 12S rRNA from all the patients and four matrilineal.2)An new nucleotide insertion was indentified in D-Loop region.3)According to the polymorphism of D-loop,this pedigree belong to mitochondrial type II.The study showed that the A1555G mutation may be one of major factors in progressive inherited deafness of this family and genetic background should be investigated in the future.     

The ND4 G11696A mutation may influence the phenotypic manifestation of the deafness-associated 12S rRNA A1555G mutation in a four-generation Chinese family

We report here the clinical, genetic and molecular characterization of a large Han Chinese family with aminoglycoside-induced and nonsyndromic hearing loss. The penetrance of hearing loss (affected matrilineal relatives/total matrilineal relatives) in this pedigree was 53%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrance of hearing loss in this pedigree was 42%. These matrilineal relatives exhibited a wide range of severity of hearing loss, varying from profound to normal hearing. Furthermore, these affected matrilineal relatives shared some common features: bilateral hearing loss of high frequencies and symmetries. Sequence analysis of mitochondrial DNA (mtDNA) in the pedigree identified the homoplasmic 12S rRNA A1555G mutation and other 35 variants belonging to Eastern Asian haplogroup D4. Of these, the V313I (G11696A) mutation in ND4 was associated with vision loss. However, the extremely low penetrance of visual loss, and the mild biochemical defect and the presence of one/167 Chinese controls indicted that the G11696A mutation is itself not sufficient to produce a clinical phenotype. Thus, the G11696A mutation may act in synergy with the primary deafness-associated 12S rRNA A1555G mutation in this Chinese family, thereby increasing the penetrance and expressivity of hearing loss in this Chinese pedigree.     

Extremely low penetrance of hearing loss in four Chinese families with the mitochondrial 12S rRNA A1555G mutation

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic, and molecular characterization of four Chinese pedigrees with aminoglycoside-induced and nonsyndromic hearing impairment. Clinical evaluation revealed the variable phenotype of hearing impairment including audiometric configuration in these subjects, although these subjects share some common features: bilateral and sensorineural hearing impairment. Strikingly, these Chinese pedigrees exhibited extremely low penetrance of hearing loss (5.2%, 4.8%, 4.2%, and 13.3%, respectively, and with an average 8% penetrance). In particular, four of all five affected matrilineal relatives of these pedigrees had aminoglycoside-induced hearing loss. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical homoplasmic A1555G mutation, associated with hearing impairment in many families from different genetic backgrounds. The fact that mtDNA of those pedigrees belonged to different haplogroups R9a, N9a, D4a, and D4 suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. However, there was the absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in these Chinese families. These data imply that the nuclear background or/and mitochondrial haplotype may not play a significant role in the phenotypic expression of the A1555G mutation in these Chinese pedigrees. However, aminoglycoside appears to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families.     

Very low penetrance of hearing loss in seven Han Chinese pedigrees carrying the deafness-associated 12S rRNA A1555G mutation

Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here the clinical, genetic and molecular characterizations of seven Han Chinese pedigrees with aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the variable phenotype of hearing impairment including severity, age-at-onset and audiometric configuration in these subjects. The penetrance of hearing loss in these pedigrees ranged from 3% to 29%, with an average of 13.6%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees varied from 0% to 17%, with an average of 5.3%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA A1555G mutation, in addition to distinct sets of mtDNA polymorphism belonging to East Asian haplogroups B4, D4, D5 and F1, respectively. This suggested that the A1555G mutation occurred sporadically and multiplied through evolution of the mtDNA in China. Despite the presence of several evolutionary conservative variants in protein-encoding genes, there was the absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in these seven Chinese families. These suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the A1555G mutation in those Chinese families with very low penetrance of hearing loss. However, aminoglycosides appear to be a major modifier factor for the phenotypic manifestation of the A1555G mutation in these Chinese families.     

Mitochondrial tRNA^Glu A14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Han Chinese family

Mutations in mitochondrial 12S rRNA gene are one of the most important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we report the characterization of one Han Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing loss. This Chinese family carrying the 12S rRNA A1555G mutation exhibited high penetrance and expressivity of heating impairment. In particular, penetrances of hearing loss in this family pedigree were 43.8% and 25%, respectively, when aminoglycoside-induced heating loss was included or excluded. Mutational analysis of entire mitochondrial genomes in this family showed the homoplasmic A1555G mutation and a set of variants belonging to haplogroup Y2. Of these, the A14693G variant occurred at the extremely conserved nucleotide （conventional position 54） of the TψC-loop of tRNA^Clu and was absent in 156 Chinese controls. Nucleotides at position 54 of tRNAs are often modified, thereby contributing to the structural formation and stabilization of functional tRNAs. Thus, the structural alteration of tRNA by the A14693G variant may lead to a failure in tRNA metabolism and impair mitochondrial protein synthesis, thereby worsening mitochondrial dysfunctions altered by the A1555G mutation. Therefore, the tRNA^Glu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated A1555G mutation in this Chinese pedigree.     

The coexistence of mitochondrial ND6 T14484C and 12S rRNA A1555G mutations in a Chinese family with Leber's hereditary optic neuropathy and hearing loss

We report here the clinical, genetic and molecular characterization of one three-generation Han Chinese family with Leber's hereditary optic neuropathy (LHON) and hearing loss. Four of 14 matrilineal relatives exhibited the moderate central vision loss at the average age of 12.5 years. Of these, one subject exhibited both LHON and mild hearing impairment. Sequence analysis of the complete mitochondrial genomes in the pedigree showed the presence of homoplasmic LHON-associated ND6 T14484C mutation, deafness-associated 12S rRNA A1555 mutation and 47 other variants belonging to Eastern Asian haplogroup H2. None of other mitochondrial variants was evolutionarily conserved and functional significance. Therefore, the coexistence of the A1555G mutation and T14484C mutations in this Chinese family indicate that the A1555G mutation may play a synergistic role in the phenotypic manifestation of LHON associated ND6 T14484C mutation. However, the incomplete penetrance of vision and hearing loss suggests the involvement of nuclear modifier genes and environmental factors in the phenotypic expression of these mtDNA mutations.     

Mitochondrial tRNAGlu 14693G variant may modulate the phenotypic manifestation of deafness-associated 12S rRNA A1555G mutation in a Hah Chinese family

Mutations in mitochondrial 12S rRNA gene are one of the most important causes of aminoglycoside-induced and nonsyndromic hearing loss. Here we report the characterization of one Han Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing loss.This Chinese family carrying the 12S rRNA A1555G mutation exhibited high penetrance and expressivity of hearing impairment. In particular, penetrances of hearing loss in this family pedigree were 43.8% and 25%, respectively, when aminoglycoside-induced heating loss was included or excluded. Mutational analysis of entire mitochondrial genomes in this family showed the homoplasmic A1555G mutation and a set of variants belonging to haplogroup Y2. Of these, the A14693G variant occurred at the extremely conserved nucleotide (conventional position 54) of the TψC-loop of tRNAGlu and was absent in 156 Chinese controls. Nucleotides at position 54 of tRNAs are often modified, thereby contributing to the structural formation and stabilization of functional tRNAs. Thus, the structural alteration of tRNA by the A14693G variant may lead to a failure in tRNA metabolism and impair mitochondrial protein synthesis, thereby worsening mitochondrial dysfunctions altered by the A1555G mutation. Therefore, the tRNAalu A14693G variant may have a potential modifier role in increasing the penetrance and expressivity of the deafness-associated AI555G mutation in this Chinese pedigree.     

Aminoglycoside-induced and non-syndromic hearing loss is associated with the G7444A mutation in the mitochondrial COI/tRNASer(UCN) genes in two Chinese families

We report here the clinical, genetic, and molecular characterization of two Chinese families with aminoglycoside induced and non-syndromic hearing impairment. Clinical and genetic evaluations revealed the variable severity and age-of-onset in hearing impairment in these families. Strikingly, there were extremely low penetrances of hearing impairment in these Chinese families. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the distinct sets of mtDNA polymorphism, in addition to the identical G7444A mutation associated with hearing loss. Indeed, the G7444A mutation in the CO1 gene and the precursor of tRNASer(UCN) gene is present in homoplasmy only in the maternal lineage of those pedigrees but not other members of these families and 164 Chinese controls. Their mitochondrial genomes belong to the Eastern Asian haplogroups C5a and D4a, respectively. In fact, the occurrence of the G7444A mutation in these several genetically unrelated subjects affected by hearing impairment strongly indicates that this mutation is involved in the pathogenesis of hearing impairment. However, there was the absence of other functionally significant mtDNA mutations in two Chinese pedigrees carrying the G7444A mutation. Therefore, nuclear modifier gene(s) or aminoglycoside(s) may play a role in the phenotypic expression of the deafness-associated G7444A mutation in these Chinese pedigrees.     

Co-occurrence of A1555G and G11778A in a Chinese family with high penetrance of Leber's hereditary optic neuropathy

Co-occurrence of double pathogenic mtDNA mutations with different claimed pathological roles in one mtDNA is infrequent. It is tentative to believe that each of these pathogenic mutations would have its own deleterious effect. Here we reported one three-generation Chinese family with a high penetrance of LHON (78.6%). Analysis of the complete mitochondrial genome in the proband revealed the presence of the LHON primary mutation G11778A in the NADH dehydrogenase 4 (ND4) gene and a deafness-associated mutation A1555G in the 12S rRNA gene. The other mtDNA variants in this family suggested a haplogroup status G2b. Although A1555G has long been confirmed to be a primary mutation for aminoglycoside-induced and non-syndromic hearing loss, none of the maternally related members in this family showed hearing impairment. It thus seems that the occurrence of A1555G in this family had no pathological manifestation. However, whether A1555G has a synergistic effect with G11778A and contribute to the high penetrance of LHON remained an open question. To our knowledge, this is the first report that identified the co-existence of a deafness mutation A1555G and a primary LHON mutation G11778A in one family.     

Molecular and Clinical Characterization of the Variable Phenotype in Korean Families with Hearing Loss Associated with the Mitochondrial A1555G Mutation

Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.