两个中国遗传性聋家系的致病基因研究
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摘要
第一部分一个母系遗传性聋家系的致病基因研究
目的：
研究一个五代母系遗传性聋大家系的遗传学病因及发病机制,阐明该家系成员耳聋的机制,为遗传性聋的防治提供理论依据。
方法：
经耳聋先证者获悉一遗传性聋大家系,经家系调查采集详细的临床及听力学资料,并在签署知情同意书后采集静脉血。由静脉血提取全基因组DNA,对母系成员的线粒体基因组全序列及常见耳聋基因GJB2经聚合酶链反应扩增和测序进行检测。对检测到的线粒体DNA耳聋相关突变应用焦磷酸测序进行异质性定量,分析突变的异质性比例与耳聋程度的相关性。对突变位点行物种间进化保守性分析。在相同遗传背景的200名正常听力对照和806名散发感音神经性聋患者中进行突变筛查。同时建立耳聋患者和正常听力对照的淋巴细胞系,提取细胞的线粒体总RNA,采用Northern blot检测基因突变后tRNA水平的变化,并进行线粒体基因的蛋白合成和细胞耗氧量测量。
结果：
该家系符合母系遗传规律,耳聋的发生与使用氨基糖甙类抗生素无关,表现为双侧对称、迟发性、进行性感音神经性聋,以高频听力损失为主,逐渐累积全频,常伴高调耳鸣。患者颞骨高分辨率CT无明显异常,未伴随明显的其他系统疾病,属于非综合征型聋。线粒体基因组全序列分析显示母系成员属于同一线粒体单倍型Z,共存在43种碱基改变,其中T12201C为异质性突变,位于tRNA—His基因二级结构的接受臂,使碱基配对由A-U变为A-C,该位点在多物种间高度保守,突变异质性比例与耳聋发病年龄和严重程度存在相关性。其余碱基改变无特殊病理意义。在200名听力正常对照和806名散发感音神经性聋患者中未筛查到该突变。常见耳聋基因GJB2筛查显示部分家系成员包括患者和听力正常者均携带235delC杂合突变。成功构建患者和正常听力对照的淋巴细胞系,Northern blot分析显示突变后tRNA-His水平较正常对照减少75%。线粒体基因的翻译产物较正常对照减少47%,细胞总耗氧率较正常对照减少36%,差异皆有统计学意义。
结论：
线粒体基因tRNA His T12201C异质性突变为该家系成员耳聋的主要分子基础,突变异质性比例与耳聋发病年龄和严重程度存在一定相关性。T12201C突变造成tRNA代谢异常,tRNA His的水平明显减少,使线粒体蛋白合成和呼吸功能显著降低,ATP合成减少,活性氧族增加,最终导致耳聋。
第二部分一个Waardenburg综合征家系的致病基因研究
目的：
研究一个中国Waardenburg综合征家系的临床表型特征和遗传学致病基因,及其基因型和表型间的关系。
方法：
经耳聋先证者获悉一个综合征型聋家系,进行家系调查、听力学检测和全身检查,并在签署知情同意书后采集静脉血5ml,提取全基因组DNA。分析整理临床资料,绘制系谱图,判断遗传方式。聚合酶链反应扩增候选基因MITF全部9个外显子及其侧翼序列,PCR产物纯化测序后与参考序列比对,寻找突变和多态改变。对发现的突变分析氨基酸及编码蛋白质的改变,并进行氨基酸多物种间保守性分析。同时对所有家系成员进行常见耳聋基因GJB2、线粒体DNA 12S rRNA的测序筛查。在100名相同遗传背景的正常听力对照中对发现的突变进行测序筛查。
结果：
该家系诊断为Waardenburg综合征Ⅱ型,主要临床表现为棕褐色雀斑、早白发、虹膜异色、先天性感音神经性聋。根据系谱图判断为常染色体显性遗传方式,但家系中不同个体的表型存在明显差异。MITF基因外显子全测序在第8外显子发现c.[742-743delAAinsT;746-747delCA]杂合突变,12名家系成员携带该突变,与临床表型共分离。突变导致MITF蛋白第248位氨基酸由赖氨酸转变为终止密码子TAG,正常时419个氨基酸残基的蛋白截短为247个氨基酸,丧失了蛋白重要的功能结构域bHLH,导致单倍剂量不足。该氨基酸位点在多物种间高度保守。同时发现先证者不仅携带MITF基因的杂合突变,而且携带GJB2基因c. [109G>A]+[235delC]复合杂合致病突变。其他家系成员无GJB2基因双致病突变,所有成员线粒体DNA 12S rRNA均未发现致病突变。100名听力正常对照中未发现MITF基因第8外显子任何突变或多态改变,也未发现GJB2基因c.[109G>A]+[235delC]复合杂合致病突变。
结论：
Waardenburg综合征Ⅱ型临床表型多变,该家系成员的主要遗传学病因为MITF基因c.[742-743delAAinsT; 746-747delCA]杂合突变,这是一个新的WS2复杂突变。先证者同时存在MITF基因突变和GJB2基因双致病突变,两个基因可能在其耳聋的表型中均发挥作用。研究拓展了WS2基因突变谱,其基因型和表型的关系需进一步研究。
Part 1 A study associated with a maternally inherited deafness family in China
Objective
To clarify the genetic etiology and pathogenesis of maternally transmitted hearing loss in a large Chinese family, for the prevention and treatment of hereditary hearing loss to provide a theoretical basis.
Methods
One Han Chinese family was ascertained through the Otology Clinic. Clinical data was obtained from this deafness family. According to the mode of inheritance through mothers, we extract the whole genome DNA in leukocyte from all family members available. PCR and sequencing the whole mitochondrion DNA and GJB2 gene to detect the possible mutation(s) associated with deafness. Pyrosequencing was used to quantitate the level of heteroplasmic mutation, which is associated with the severity and age-at-onset of hearing loss. The mutation of evolutionary conservation is calculated by comparing the human mtDNA variants with other species. Steady-state level of mitochondrial RNAs was examined by use lymphobastoid cell lines from affected matrilineal relatives and controls. These cell lines were further assessed for the effects of the mitochondrial protein synthesis and endogenous respiration.
Results
The maternal family members had symmetrical, late-onset deafness, which began with tinnitus and high-frequency hearing loss, and the deafness was independence with use of aminoglycoside antibiotics. A CT scan of temporal bones of proband is normal. There is no other significant abnormal in this family. The mitochondrial DNA in this family has 43 mutations, belongs to haplotype Z. A novel heteroplasmic mutation T12201C in tRNA His of mitochondrial DNA had been found, which disrupts a highly conservative base-pairing (5A-68U) on the acceptor stem of tRNA His. The level of heteroplasmy in T12201C was roughly correlated with the age of onset and degree of deafness. No other mutations had been found important in mitochondrial DNA. Heterotic 235 delC in GJB2 gene had been found in seven maternal members including both deafness and normal hearing persons. Mitochondrial tRNA Northern analysis revealed that the T12201C mutation caused 75% reduction in steady-state levels of tRNA His,47% reduction in the rate of mitochondrial translation, and 37% reduction in the rate of total O2 consumption in the lymphoblastoid cell lines compared to the controls. The difference was statistically significant.
Conclusions
A novel heteroplasmic mutation T12201C in tRNA His of mitochondrion DNA is mostly possible mutation induced the maternally inherited deafness in this family. A failure in tRNA metabolism causes a significant decrease in mitochondrial protein synthesis and respiratory phenotype, which results in a decline in ATP production and increasing production of oxygen reactive species, and eventually hearing loss. The level of heteroplasmic T12201C is associated with the age of onset and the degree of deafness. Further more, the tissue-specificity of this pathogenic mtDNA mutation is likely duie to the involvement of nuclear modifier genes or tissue-specific differences in tRNA metabolism.
Part 2
The deafness of Waardenburg Syndrome typeⅡin a Chinese family
Objective
To investigate clinical and molecular features, relationship between phenotype and genotype in a large Chinese Waardenburg Syndrome family.
Methods
A family we obtained was identified with Waardenburg Syndrome in China. The proband with WS2 was discovered in clinic service, and then intimate clinic information and venous blood were collected in each member available by family investigation in their hometown. The whole genome DNA was extracted, and all 9 exons of MITF gene and the frequent hereditary deafness genes GJB2 and mitochondrial DNA (mtDNA) 12S rRNA were detected simultaneously by polymerase chain reaction (PCR). The mutations were analyzed and compared with the reference sequence to definite the genetic reason of WS2 in this family. We determined whether the gene mutations lead to changes of amino acids and evolution conservatism analysis of amino acids in MITF protein was made across many species. Screening the mutation discovered in one hundred controls with the same genetic background.
Results
According to the clinical features, it is consistent with WS2 diagnostic criteria previously described. The main abnormalities are sensorineural deafness, brown freckles on the skin, premature graying, and heterochromia irides in this family, but no dystopia canthorum in any person. The pedigree chart demonstrates autosomal dominant inheritance, but family members show varying degrees of clinical manifestation. An interesting novel heterozygous mutation c. [742-743delAAinsT; 746-747delCA] has been found in MITF gene exon 8. Twelve members have the mutation, which is co-segregate with phenotype of WS2 in the family. This mutation leads to an advanced termination codon TAG, which makes a truncated protein with only 247 amino acids, compared with the 419 amino acids in normal protein. The mutation makes MITF protein lost the complete functional structural domain bHLH-Zip, and leads to haploinsufficiency. This amino acid K (Lys) is highly conserved among many species. Intriguingly, the deaf proband had MITF gene heterozygous mutation as well as GJB2 gene c. [109G>A]+[235delC] compound heterozygous pathogenic mutations, which also lead to hereditary deafness. Nobody except the proband has double recessive pathogenic mutations in GJB2 gene and no pathogenic variants in mtDNA 12S rRNA gene are identified in all members of this pedigree. Meanwhile, no any mutation or polymorphism was observed in exon 8 of MITF gene in one hundred normal hearing controls with the same genetic background and c. [109G>A]+[235delC] in GJB2 gene was also not found in one hundred controls.
Conclusions
WS2 has multivariate clinical phenotype, the novel rare pattern of inconsecutive heterozygous mutation, c. [742-743delAAinsT; 746-747delCA], in MITF gene exon 8 was the main genetic etiology of this WS2 family. The proband has both GJB2 gene and MITF gene mutations. Therefore, a digenic effect may happen in the deafness of proband with MITF and GJB2 genes. This new miscellaneous frameshift mutation in MITF gene expands mutation databases of WS2A in chinese patients. Relationship between phenotype and genotype of this family needs to be studied further in the future.
目的：
研究一个五代母系遗传性聋大家系的遗传学病因及发病机制,阐明该家系成员耳聋的机制,为遗传性聋的防治提供理论依据。
方法：
经耳聋先证者获悉一遗传性聋大家系,经家系调查采集详细的临床及听力学资料,并在签署知情同意书后采集静脉血。由静脉血提取全基因组DNA,对母系成员的线粒体基因组全序列及常见耳聋基因GJB2经聚合酶链反应扩增和测序进行检测。对检测到的线粒体DNA耳聋相关突变应用焦磷酸测序进行异质性定量,分析突变的异质性比例与耳聋程度的相关性。对突变位点行物种间进化保守性分析。在相同遗传背景的200名正常听力对照和806名散发感音神经性聋患者中进行突变筛查。同时建立耳聋患者和正常听力对照的淋巴细胞系,提取细胞的线粒体总RNA,采用Northern blot检测基因突变后tRNA水平的变化,并进行线粒体基因的蛋白合成和细胞耗氧量测量。
结果：
该家系符合母系遗传规律,耳聋的发生与使用氨基糖甙类抗生素无关,表现为双侧对称、迟发性、进行性感音神经性聋,以高频听力损失为主,逐渐累积全频,常伴高调耳鸣。患者颞骨高分辨率CT无明显异常,未伴随明显的其他系统疾病,属于非综合征型聋。线粒体基因组全序列分析显示母系成员属于同一线粒体单倍型Z,共存在43种碱基改变,其中T12201C为异质性突变,位于tRNA—His基因二级结构的接受臂,使碱基配对由A-U变为A-C,该位点在多物种间高度保守,突变异质性比例与耳聋发病年龄和严重程度存在相关性。其余碱基改变无特殊病理意义。在200名听力正常对照和806名散发感音神经性聋患者中未筛查到该突变。常见耳聋基因GJB2筛查显示部分家系成员包括患者和听力正常者均携带235delC杂合突变。成功构建患者和正常听力对照的淋巴细胞系,Northern blot分析显示突变后tRNA-His水平较正常对照减少75%。线粒体基因的翻译产物较正常对照减少47%,细胞总耗氧率较正常对照减少36%,差异皆有统计学意义。
结论：
线粒体基因tRNA His T12201C异质性突变为该家系成员耳聋的主要分子基础,突变异质性比例与耳聋发病年龄和严重程度存在一定相关性。T12201C突变造成tRNA代谢异常,tRNA His的水平明显减少,使线粒体蛋白合成和呼吸功能显著降低,ATP合成减少,活性氧族增加,最终导致耳聋。
第二部分一个Waardenburg综合征家系的致病基因研究
目的：
研究一个中国Waardenburg综合征家系的临床表型特征和遗传学致病基因,及其基因型和表型间的关系。
方法：
经耳聋先证者获悉一个综合征型聋家系,进行家系调查、听力学检测和全身检查,并在签署知情同意书后采集静脉血5ml,提取全基因组DNA。分析整理临床资料,绘制系谱图,判断遗传方式。聚合酶链反应扩增候选基因MITF全部9个外显子及其侧翼序列,PCR产物纯化测序后与参考序列比对,寻找突变和多态改变。对发现的突变分析氨基酸及编码蛋白质的改变,并进行氨基酸多物种间保守性分析。同时对所有家系成员进行常见耳聋基因GJB2、线粒体DNA 12S rRNA的测序筛查。在100名相同遗传背景的正常听力对照中对发现的突变进行测序筛查。
结果：
该家系诊断为Waardenburg综合征Ⅱ型,主要临床表现为棕褐色雀斑、早白发、虹膜异色、先天性感音神经性聋。根据系谱图判断为常染色体显性遗传方式,但家系中不同个体的表型存在明显差异。MITF基因外显子全测序在第8外显子发现c.[742-743delAAinsT;746-747delCA]杂合突变,12名家系成员携带该突变,与临床表型共分离。突变导致MITF蛋白第248位氨基酸由赖氨酸转变为终止密码子TAG,正常时419个氨基酸残基的蛋白截短为247个氨基酸,丧失了蛋白重要的功能结构域bHLH,导致单倍剂量不足。该氨基酸位点在多物种间高度保守。同时发现先证者不仅携带MITF基因的杂合突变,而且携带GJB2基因c. [109G>A]+[235delC]复合杂合致病突变。其他家系成员无GJB2基因双致病突变,所有成员线粒体DNA 12S rRNA均未发现致病突变。100名听力正常对照中未发现MITF基因第8外显子任何突变或多态改变,也未发现GJB2基因c.[109G>A]+[235delC]复合杂合致病突变。
结论：
Waardenburg综合征Ⅱ型临床表型多变,该家系成员的主要遗传学病因为MITF基因c.[742-743delAAinsT; 746-747delCA]杂合突变,这是一个新的WS2复杂突变。先证者同时存在MITF基因突变和GJB2基因双致病突变,两个基因可能在其耳聋的表型中均发挥作用。研究拓展了WS2基因突变谱,其基因型和表型的关系需进一步研究。
Part 1 A study associated with a maternally inherited deafness family in China
Objective
To clarify the genetic etiology and pathogenesis of maternally transmitted hearing loss in a large Chinese family, for the prevention and treatment of hereditary hearing loss to provide a theoretical basis.
Methods
One Han Chinese family was ascertained through the Otology Clinic. Clinical data was obtained from this deafness family. According to the mode of inheritance through mothers, we extract the whole genome DNA in leukocyte from all family members available. PCR and sequencing the whole mitochondrion DNA and GJB2 gene to detect the possible mutation(s) associated with deafness. Pyrosequencing was used to quantitate the level of heteroplasmic mutation, which is associated with the severity and age-at-onset of hearing loss. The mutation of evolutionary conservation is calculated by comparing the human mtDNA variants with other species. Steady-state level of mitochondrial RNAs was examined by use lymphobastoid cell lines from affected matrilineal relatives and controls. These cell lines were further assessed for the effects of the mitochondrial protein synthesis and endogenous respiration.
Results
The maternal family members had symmetrical, late-onset deafness, which began with tinnitus and high-frequency hearing loss, and the deafness was independence with use of aminoglycoside antibiotics. A CT scan of temporal bones of proband is normal. There is no other significant abnormal in this family. The mitochondrial DNA in this family has 43 mutations, belongs to haplotype Z. A novel heteroplasmic mutation T12201C in tRNA His of mitochondrial DNA had been found, which disrupts a highly conservative base-pairing (5A-68U) on the acceptor stem of tRNA His. The level of heteroplasmy in T12201C was roughly correlated with the age of onset and degree of deafness. No other mutations had been found important in mitochondrial DNA. Heterotic 235 delC in GJB2 gene had been found in seven maternal members including both deafness and normal hearing persons. Mitochondrial tRNA Northern analysis revealed that the T12201C mutation caused 75% reduction in steady-state levels of tRNA His,47% reduction in the rate of mitochondrial translation, and 37% reduction in the rate of total O2 consumption in the lymphoblastoid cell lines compared to the controls. The difference was statistically significant.
Conclusions
A novel heteroplasmic mutation T12201C in tRNA His of mitochondrion DNA is mostly possible mutation induced the maternally inherited deafness in this family. A failure in tRNA metabolism causes a significant decrease in mitochondrial protein synthesis and respiratory phenotype, which results in a decline in ATP production and increasing production of oxygen reactive species, and eventually hearing loss. The level of heteroplasmic T12201C is associated with the age of onset and the degree of deafness. Further more, the tissue-specificity of this pathogenic mtDNA mutation is likely duie to the involvement of nuclear modifier genes or tissue-specific differences in tRNA metabolism.
Part 2
The deafness of Waardenburg Syndrome typeⅡin a Chinese family
Objective
To investigate clinical and molecular features, relationship between phenotype and genotype in a large Chinese Waardenburg Syndrome family.
Methods
A family we obtained was identified with Waardenburg Syndrome in China. The proband with WS2 was discovered in clinic service, and then intimate clinic information and venous blood were collected in each member available by family investigation in their hometown. The whole genome DNA was extracted, and all 9 exons of MITF gene and the frequent hereditary deafness genes GJB2 and mitochondrial DNA (mtDNA) 12S rRNA were detected simultaneously by polymerase chain reaction (PCR). The mutations were analyzed and compared with the reference sequence to definite the genetic reason of WS2 in this family. We determined whether the gene mutations lead to changes of amino acids and evolution conservatism analysis of amino acids in MITF protein was made across many species. Screening the mutation discovered in one hundred controls with the same genetic background.
Results
According to the clinical features, it is consistent with WS2 diagnostic criteria previously described. The main abnormalities are sensorineural deafness, brown freckles on the skin, premature graying, and heterochromia irides in this family, but no dystopia canthorum in any person. The pedigree chart demonstrates autosomal dominant inheritance, but family members show varying degrees of clinical manifestation. An interesting novel heterozygous mutation c. [742-743delAAinsT; 746-747delCA] has been found in MITF gene exon 8. Twelve members have the mutation, which is co-segregate with phenotype of WS2 in the family. This mutation leads to an advanced termination codon TAG, which makes a truncated protein with only 247 amino acids, compared with the 419 amino acids in normal protein. The mutation makes MITF protein lost the complete functional structural domain bHLH-Zip, and leads to haploinsufficiency. This amino acid K (Lys) is highly conserved among many species. Intriguingly, the deaf proband had MITF gene heterozygous mutation as well as GJB2 gene c. [109G>A]+[235delC] compound heterozygous pathogenic mutations, which also lead to hereditary deafness. Nobody except the proband has double recessive pathogenic mutations in GJB2 gene and no pathogenic variants in mtDNA 12S rRNA gene are identified in all members of this pedigree. Meanwhile, no any mutation or polymorphism was observed in exon 8 of MITF gene in one hundred normal hearing controls with the same genetic background and c. [109G>A]+[235delC] in GJB2 gene was also not found in one hundred controls.
Conclusions
WS2 has multivariate clinical phenotype, the novel rare pattern of inconsecutive heterozygous mutation, c. [742-743delAAinsT; 746-747delCA], in MITF gene exon 8 was the main genetic etiology of this WS2 family. The proband has both GJB2 gene and MITF gene mutations. Therefore, a digenic effect may happen in the deafness of proband with MITF and GJB2 genes. This new miscellaneous frameshift mutation in MITF gene expands mutation databases of WS2A in chinese patients. Relationship between phenotype and genotype of this family needs to be studied further in the future.
引文
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