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1.
线粒体DNA G7444A突变可能影响A1555G突变的表型表达 总被引:2,自引:2,他引:0
线粒体12S rRNA和tRNASer(UCN) 基因是导致非综合征型听力损失的两个突变热点区域。作者收集了1个母系遗传感音神经性聋家系, 该家系同时携带线粒体DNA (mtDNA) A1555G和G7444A突变。临床资料分析表明, 该家系包括药物致聋的耳聋外显率(所有耳聋患者/所有母系成员)为58%, 而非药物致聋的耳聋外显率(非药物性聋患者/所有母系成员)为25%, 明显高于其他携带A1555G突变的耳聋家系。先证者的线粒体全序列分析表明, 该线粒体基因组共有28个多态位点, 属于东亚人群B4c1单体型。在这些多态位点中, 除A1555G和G7444A突变外, 未发现其他有功能意义的突变。这表明mtDNA G7444A突变可能加重由A1555G突变造成的线粒体功能缺失, 从而增加耳聋的外显率。 相似文献
2.
Mitochondrial rRNA and tRNA and hearing function 总被引:2,自引:0,他引:2
3.
Forli F Passetti S Mancuso M Seccia V Siciliano G Nesti C Berrettini S 《Bioscience reports》2007,27(1-3):113-123
Mitochondrial diseases (MD) are a clinically heterogeneous group of disorders that arise as a result of dysfunction of the
mitochondrial respiratory chain. Sensorineural hearing loss (SNHL) is often associated to mitochondrial dysfunctions both
in syndromic, nonsyndromic forms. SNHL has been described in association to different mitochondrial multisystemic syndromes,
often characterized by an important neuromuscular involvement. Because of the clinical relevance of the associated neurological
symptoms, the occurrence of SNHL is often underestimated and undiagnosed. In this study we evaluated the incidence of SNHL
in a group of 17 patients with MD. We detected some degree of hearing impairment in 8/17 patients (47%), thus confirming the
frequency of hearing impairment in MD. Furthermore, we want to highlight the role of the audiologist and otolaryngologist
in the diagnosis and characterization of a MD, which should be suspected in all the cases in which the hearing loss is associated
to signs and symptoms characteristic of mitochondrial dysfunction, especially if the family history is positive for hearing
loss or MD in the maternal line. 相似文献
4.
Yuan H Chen J Liu X Cheng J Wang X Yang L Yang S Cao J Kang D Dai P Zhai S Han D Young WY Guan MX 《Biochemical and biophysical research communications》2007,362(1):94-100
Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families. The penetrances of hearing loss in these pedigrees were 20% and 18%, when aminoglycoside-induced deafness was included. When the effect of aminoglycosides was excluded, the penetrances of hearing loss in these seven pedigrees were 10% and 15%. Sequence analysis of the complete mitochondrial genomes in these pedigrees showed the presence of the deafness-associated 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations. Their distinct sets of mtDNA polymorphism belonged to Eastern Asian haplogroup C4a1, while other previously identified six Chinese mitochondrial genomes harboring the C1494T mutation belong to haplogroups D5a2, D, R, and F1, respectively. This suggested that the C1494T or G7444A mutation occurred sporadically and multiplied through evolution of the mitochondrial DNA (mtDNA). The absence of functionally significant mutations in tRNA and rRNAs or secondary LHON mutations in their mtDNA suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in those Chinese families. However, aminoglycosides and other nuclear modifier genes play a modifying role in the phenotypic manifestation of the C1494T mutation in these Chinese families. 相似文献
5.
Mutations in mitochondrial DNA (mtDNA) are one of the most important causes of hearing loss. Of these, the homoplasmic A1555G and C1494T mutations at the highly conserved decoding site of the 12S rRNA gene are well documented as being associated with either aminoglycoside-induced or nonsyndromic hearing loss in many families worldwide. Moreover, five mutations associated with nonsyndromic hearing loss have been identified in the tRNASer(UCN) gene: A7445G, 7472insC, T7505C, T7510C, and T7511C. Other mtDNA mutations associated with deafness are mainly located in tRNA and protein-coding genes. Failures in mitochondrial tRNA metabolism or protein synthesis were observed from cybrid cells harboring these primary mutations, thereby causing the mitochondrial dysfunctions responsible for deafness. This review article provides a detailed summary of mtDNA mutations that have been reported in deafness and further discusses the molecular mechanisms of these mtDNA mutations in deafness expression. 相似文献
6.
L. U. Dzhemilova O. L. Posukh A. M. Tazetdinov N. A. Barashkov S. A. Zhuravskii S. N. Ponidelko T. G. Markova V. N. Tadinova S. A. Fedorova N. R. Maksimova E. K. Khusnutdinova 《Russian Journal of Genetics》2009,45(7):861-869
Mitochondrial DNA (mtDNA) mutations play an important role in etiology of hereditary hearing loss. In various regions of the world, patients suffer from nonsyndromic sensorineural hearing loss initiated by aminoglycoside antibiotics. Mutations that had been shown as pathogenetically important for hearing function disturbance were identified in mitochondrial 12S rRNA and tRNA Ser(UCN) genes while pathogenic role of several mtDNA sequences requires additional studies. Here we examined various mutations and polymorphisms in mitochondrial 12S rRNA and tRNA Ser(UCN) genes in 410 patients with nonsyndromic sensorineural hearing loss from Volga-Ural, St. Petersburg, Yakutiya and Altai regions and in 520 individuals with normal hearing, which represented several ethnic groups (Russians, Tatars, Bashkirs, Yakuts, and Altaians) dwelling in Russian Federation. The A1555 (12S rRNA) mutation, which is important in disease pathogenesis, was detected in two families from Yakutiya and St. Petersburg with a hearing loss likely induced by aminoglycoside treatment as well as in a sample of Yakut population with a frequency of 0.83%. Further studies are required to reveal the importance of the detected 961 insC, 961 insC (n), 961 delTinsC (n), T 961 G, T 1095 C (12 S rRNA), as well as G7444A and G 7444 A, A 7445 C (tRNA Ser (UCN) ) mutations in the disturbance of hearing in patients. In addition, mitochondtrial DNA polymorphisms similar to those in European and Asian populations in spectrum and frequency, were revealed in the patients and the individuals from population samples. 相似文献
7.
Pathogenicity of two COQ7 mutations and responses to 2,4‐dihydroxybenzoate bypass treatment
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Ying Wang Christopher Smith Jillian S. Parboosingh Aneal Khan Micheil Innes Siegfried Hekimi 《Journal of cellular and molecular medicine》2017,21(10):2329-2343
Primary ubiquinone (co‐enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6‐year‐old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction. The severity of L111P is enhanced by the particular COQ7 polymorphism (T103M) that the patient carries, but not by a mitochondrial DNA mutation (A1555G) that is also present in the patient and that has been linked to aminoglycoside‐dependent hearing loss. We analysed treatment with the unnatural biosynthesis precursor 2,4‐dihydroxybenzoate (DHB), which can restore ubiquinone synthesis in cells completely lacking the enzymatic activity of COQ7. We find that the treatment is not beneficial for every COQ7 mutation and its outcome depends on the extent of enzyme activity loss. 相似文献
8.
线粒体DNA突变是引起听力损伤的重要原因之一. 其中,线粒体12S rRNA基因突变与综合征型耳聋和非综合征型耳聋相关. 导致综合征型耳聋的线粒体DNA突变多为异质性,然 而对于非综合征型耳聋突变则多以同质性或高度异质性存在,说明这种分子致病性需要较高的阈值. 位于12S rRNA解码区的A1555G和C1494T突变是造成氨基糖甙类抗生素耳毒性和 非综合征型耳聋常见的分子机制. 这些突变可能造成12S rRNA二级结构的改变,影响线粒体蛋白质的合成,降低细胞内ATP的产生,由此引起的线粒体功能障碍导致耳聋. 但是多数 基因突变的致病机制还仅处于推测阶段. 其它修饰因子如氨基糖甙类抗生素、线粒体单体型、核修饰基因参与了线粒体12S rRNA基因A1555G和C1494T突变相关的耳聋表型表达. 相似文献
9.
Disorders caused by mitochondrial respiratory chain deficiency due to mutations in mitochondrial DNA have varied phenotypes but many involve neurological features often associated with cell loss within specific brain regions. These disorders, along with the increasing evidence of decline in mitochondrial function with ageing, have raised speculation that primary changes in mitochondria could have an important role in age-related neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). Evidence supporting a role for mitochondria in common neurodegenerative diseases comes from studies with the toxin MPP+ and familial PD, which has been shown to involve proteins such as DJ-1 and Pink1 (both of which are predicted to have a role in mitochondrial function and oxidative stress). Mutations within the mitochondrial genome have been shown to accumulate with age and in common neurodegenerative diseases. Mitochondrial DNA haplogroups have also been shown to be associated with certain neurodegenerative conditions. This review covers the primary mitochondrial diseases but also discuss the potential role of mitochondria and mitochondrial DNA mutations in mitochondrial and neurodegenerative diseases, in particular in PD and in AD. 相似文献
10.
Mitochondrial tRNA mutations are one of the important causes of both syndromic and non-syndromic deafness. Of those, syndromic deafness-associated tRNA mutations such as tRNA(Leu(UUR)) 3243A>G are often present in heteroplasmy, while non-syndromic deafness-associated tRNA mutations including tRNA(Ser(UCN)) 7445A>G often occur in homplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary mutations leading to hearing loss. However, other tRNA mutations such as tRNA(Thr) 15927G>A and tRNA(Ser(UCN)) 7444G>A may act in synergy with the primary mitochondrial DNA mutations, modulating the phenotypic manifestation of the primary mitochondrial DNA mutations. Theses tRNA mutations cause structural and functional alteration. A failure in tRNA metabolism caused by these tRNA mutations impaired mitochondrial translation and respiration, thereby causing mitochondrial dysfunctions responsible for deafness. These data offer valuable information for the early diagnosis, management and treatment of maternally inherited deafness. 相似文献
11.
Mutational analysis of the mitochondrial 12S rRNA gene in Chinese pediatric subjects with aminoglycoside-induced and non-syndromic hearing loss 总被引:11,自引:0,他引:11
Li Z Li R Chen J Liao Z Zhu Y Qian Y Xiong S Heman-Ackah S Wu J Choo DI Guan MX 《Human genetics》2005,117(1):9-15
Mutations in mitochondrial DNA (mtDNA) have been found to be associated with sensorineural hearing loss. We report here a systematic mutational screening of the mitochondrial 12S rRNA gene in 128 Chinese pediatric subjects with sporadic aminoglycoside-induced and non-syndromic hearing loss. We show that aminoglycoside ototoxicity accounts for 48% of cases of hearing loss in this Chinese pediatric population. Of the known deafness-associated mutations in this gene, the incidence of the A1555G mutation is ~13% and ~2.9% in this Chinese pediatric population with aminoglycoside-induced and non-syndromic hearing loss, respectively. Furthermore, mutations at position 961 in the 12S rRNA gene account for ~1.7% and 4.4% of cases of aminoglycoside-induced and non-syndromic hearing loss in this Chinese clinical population, respectively. The T1095C mutation has been identified in one maternally inherited family with aminoglycoside-induced and non-syndromic hearing loss. However, the C1494T mutation was not detected in this clinical population. In addition, three variants, A827G, T1005C and A1116G, in the 12S rRNA gene, localized at highly conserved sites, may play a role in the pathogenesis of aminoglycoside ototoxicity. These data strongly suggest that the mitochondrial 12S rRNA is a hot-spot for deafness-associated mutations in the Chinese population.Z. Li and R. Li contributed equally to this work. 相似文献
12.
Tang X Yang L Zhu Y Liao Z Wang J Qian Y Tao Z Hu L Wu G Lan J Wang X Ji J Wu J Ji Y Feng J Chen J Li Z Zhang X Lu J Guan MX 《Gene》2007,393(1-2):11-19
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. 相似文献
13.
线粒体DNA突变与许多人类疾病的发病机制相关。文章报道1例典型的患有耳聋与癫痫症状的具有母系遗传特征的中国家系。该家系共3代人, 其中14名母系成员中有3名耳聋患者, 3名癫痫患者, 而其他成员则无临床症状。线粒体全基因组序列分析表明, tRNASer(UCN)基因7472delC新突变和33个多态位点属于东亚单体型B4b1a2。7472delC突变位于tRNASer(UCN)高度保守的T-arm上。而在该区域的相同位点7472insC突变已在多个无遗传相关的家系中被发现与耳聋和癫痫相关。7472insC突变使tRNA代谢和线粒体功能产生缺陷。这样与7472insC突变相近的7472delC突变可能也会以相似机制引起线粒体功能障碍。同时, 在该家系中未发现GJB2基因及其他线粒体基因突变。因此, tRNASer(UCN) 7472delC可能是耳聋与癫痫相关的线粒体基因新突变。 相似文献
14.
Berrettini S Forli F Passetti S Rocchi A Pollina L Cecchetti D Mancuso M Siciliano G 《Bioscience reports》2008,28(1):49-59
Over the last decade, a number of distinct mutations in the mtDNA (mitochondrial DNA) have been found to be associated with both syndromic and non-syndromic forms of hearing impairment. Their real incidence as a cause of deafness is poorly understood and generally underestimated. Among the known mtDNA mutations, the A1555G mutation in the 12S gene has been identified to be one of the most common genetic cause of deafness, and it has been described to be both associated to non-syndromic progressive SNHL (sensorineural hearing loss) and to aminoglycoside-induced SNHL. In the present study, we have investigated the presence of mtDNA alterations in patients affected by idiopathic non-syndromic SNHL, both familiar and sporadic, in order to evaluate the frequency of mtDNA alterations as a cause of deafness and to describe the audiological manifestations of mitochondrial non-syndromic SNHL. In agreement with previous studies, we found the A1555G mutation to be responsible for a relevant percentage (5.4%) of cases affected with isolated idiopathic sensorineural hearing impairment. 相似文献
15.
Extremely low penetrance of hearing loss in four Chinese families with the mitochondrial 12S rRNA A1555G mutation 总被引:8,自引:0,他引:8
Young WY Zhao L Qian Y Wang Q Li N Greinwald JH Guan MX 《Biochemical and biophysical research communications》2005,328(4):1244-1251
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. 相似文献
16.
Guan MX 《Mitochondrion》2011,11(2):237-245
The mitochondrial 12S rRNA is a hot spot for mutations associated with both aminoglycoside-induced and nonsyndromic hearing loss. Of those, the homoplasmic 1555A>G and 1494C>T mutations at the highly conserved decoding region of the 12S rRNA have been associated with hearing loss worldwide. In particular, these two mutations account for a significant number of cases of aminoglycoside ototoxicity. The 1555A>G or 1494C>T mutation is expected to form a novel 1494C-G1555 or 1494U-A1555 base-pair at the highly conserved A-site of 12S rRNA. These transitions make the human mitochondrial ribosomes more bacteria-like and alter binding sites for aminoglycosides. As a result, the exposure to aminoglycosides can induce or worsen hearing loss in individuals carrying one of these mutations. Biochemical characterization demonstrated an impairment of mitochondrial protein synthesis and subsequent defects in respiration in cells carrying the A1555G or 1494C>T mutation. Furthermore, a wide range of severity, age-at-onset and penetrance of hearing loss was observed within and among families carrying these mutations. Nuclear modifier genes, mitochondrial haplotypes and aminoglycosides should modulate the phenotypic manifestation of the 12S rRNA 1555A>G and 1494C>T mutations. Therefore, these data provide valuable information and technology: (1) to predict which individuals are at risk for ototoxicity; (2) to improve the safety of aminoglycoside antibiotic therapy; and (3) eventually to decrease the incidence of hearing loss. 相似文献
17.
Paolo Puddu Giovanni M Puddu Eleonora Cravero Susanna De Pascalis Antonio Muscari 《Journal of biomedical science》2009,16(1):112-9
An important role in atherogenesis is played by oxidative stress, which may be induced by common risk factors. Mitochondria
are both sources and targets of reactive oxygen species, and there is growing evidence that mitochondrial dysfunction may
be a relevant intermediate mechanism by which cardiovascular risk factors lead to the formation of vascular lesions. Mitochondrial
DNA is probably the most sensitive cellular target of reactive oxygen species. Damage to mitochondrial DNA correlates with
the extent of atherosclerosis. Several cardiovascular risk factors are demonstrated causes of mitochondrial damage. Oxidized
low density lipoprotein and hyperglycemia may induce the production of reactive oxygen species in mitochondria of macrophages
and endothelial cells. Conversely, reactive oxygen species may favor the development of type 2 diabetes mellitus, mainly through
the induction of insulin resistance. Similarly - in addition to being a cause of endothelial dysfunction, reactive oxygen
species and subsequent mitochondrial dysfunction - hypertension may develop in the presence of mitochondrial DNA mutations.
Finally, other risk factors, such as aging, hyperhomocysteinemia and cigarette smoking, are also associated with mitochondrial
damage and an increased production of free radicals. So far clinical studies have been unable to demonstrate that antioxidants
have any effect on human atherogenesis. Mitochondrial targeted antioxidants might provide more significant results. 相似文献
18.
《BBA》2006,1757(5-6):611-617
The accumulation of mitochondrial DNA mutations has been proposed as a potential mechanism in the physiological processes of ageing and age-related disease. Although mitochondria have long been anticipated as a perpetrator of ageing, there was little experimental evidence to link these changes directly with the cellular pathology of ageing. Recently, considerable progress in understanding basic mitochondrial genetics and in identifying acquired mtDNA mutations in ageing has been made. Furthermore, the creation of mtDNA-mutator mice has provided the first direct evidence that accelerating the mtDNA mutation rate can result in premature ageing, consistent with the view that loss of mitochondrial function is a major causal factor in ageing. This review will, therefore, focus on recent developments in ageing research related to the role played by mtDNA. 相似文献
19.
Wardell TM Ferguson E Chinnery PF Borthwick GM Taylor RW Jackson G Craft A Lightowlers RN Howell N Turnbull DM 《Mutation research》2003,525(1-2):19-27
Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in human cells. The mitochondrial genome encodes essential information for the synthesis of the mitochondrial respiratory chain. Inherited defects of this genome are an important cause of human disease. In addition, the mitochondrial genome seems to be particularly prone to DNA damage and acquired mutations may have a role in ageing, cancer and neurodegeneration. We wished to determine if radiotherapy and chemotherapy used in the treatment of cancer could induce changes in the mitochondrial genome. Such changes would be an important genetic marker of DNA damage and may explain some of the adverse effects of treatment. We studied samples from patients who had received radiotherapy and chemotherapy for point mutations within the mtDNA control region, and for large-scale deletions. In blood samples from patients, we found a significantly increased number of point mutations compared to the control subjects. In muscle biopsies from 7 of 8 patients whom had received whole body irradiation as well as chemotherapy, the level of a specific mtDNA deletion was significantly greater than in control subjects. Our studies have shown that in patients who have been treated for cancer there is an increased level of mtDNA damage. 相似文献
20.
Mitochondrial DNA and ageing 总被引:6,自引:0,他引:6
Trifunovic A 《Biochimica et biophysica acta》2006,1757(5-6):611-617
The accumulation of mitochondrial DNA mutations has been proposed as a potential mechanism in the physiological processes of ageing and age-related disease. Although mitochondria have long been anticipated as a perpetrator of ageing, there was little experimental evidence to link these changes directly with the cellular pathology of ageing. Recently, considerable progress in understanding basic mitochondrial genetics and in identifying acquired mtDNA mutations in ageing has been made. Furthermore, the creation of mtDNA-mutator mice has provided the first direct evidence that accelerating the mtDNA mutation rate can result in premature ageing, consistent with the view that loss of mitochondrial function is a major causal factor in ageing. This review will, therefore, focus on recent developments in ageing research related to the role played by mtDNA. 相似文献