Analysis of audiological characteristics and genetic background in patients with nonsyndromic deafness and mitochondrial DNA 1555A>G mutation / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze the audiological features and genetic background of patients carrying mitochondrial DNA(mtDNA) 1555A>G mutation and factors which may influence the extent of nonsyndromic hearing loss associated with the mutation.</p><p><b>METHODS</b>A literature search was carried out on databases including PubMed, CNKI, Wanfang, and VIP. Combined with author's data, the clinical features of the patients, in particular audiological characteristics, were summarized.</p><p><b>RESULTS</b>A total of 857 effective cases were collected and analyzed. A significantly correlation was identified between history of aminoglycosides exposure and extent of hearing loss, in addition with a negative correlation between the age of onset and extent of hearing-impairment. Drug exposure was corelated with the age of onset but independent to the loss of high-frequency hearing loss. Heteroplasmies had a reverse correlation with the degree of hearing loss. Among the haplotypes of mitochondrial DNA, haplotype D was the most common one, while haplotype B had the highest penetrance.</p><p><b>CONCLUSION</b>Nonsyndromic hearing loss associated with mitochondrial DNA 1555A>G mutation is influenced by factors such as aminoglycosides exposure, age, proportion of mutation, and haplotype of the mitochondrial DNA. Analysis of clinical cases is critical for identifying individuals carrying deafness susceptibility mutations and is the first step for early diagnosis.</p>

Modification factors associated with maternally inherited non-syndromic hearing loss / 中华耳鼻咽喉头颈外科杂志

Mutations in the mitochondrial DNA have been certified to be one of the most important causes of maternally inherited sensorineural hearing loss. Among these, mitochondrial 12S rRNA1555A>G, 1494C>T and other mutations are associated with both nonsyndromic and drug induced hearing loss caused by aminoglycosides. Individuals carrying 1555A>G or 1494C>T mutation have a variety of clinical manifestations, which implies that the 1555A>G or 1494C>T mutation is a chief factor underlying the development of deafness but insufficient to produce the clinical phenotype. Therefore other modifier factors, such as aminoglycosides, mitochondrial haplotypes, secondary mutation or nuclear modifier genes, may play an important role in the phenotypic expression of the deafness-associated mitochondrial 12S rRNA1555A>G or 1494C>T mutation. In this review, the modifier factors for the phenotypic expression of deafness-associated mitochondrial 12S rRNA1555A>G or 1494C>T mutations were summarized and proposed the pathogenesis of maternally inherited deafness.

Mutations of mitochondrial tRNAand their connection with hearing loss / 中华医学遗传学杂志

Mitochondrial tRNAgene mutation is closely related to acoustic nerve deafness. Some mutations can affect the structure and transcriptional processing of tRNA, for instance m.7444G>A mutation in tRNAprecursor 3' side, m.7472 insC as well as m.7511T>C mutations in the stem and ring of tRNA, may influence tRNAstability, thus affect the synthesis of mitochondrial peptides, reduce the production of ATP and cause deafness. This article focuses on mitochondrial tRNAgene mutations as well as the mechanism underlying hearing loss.

Mitochondrial tRNA(Thr)T15943C mutation may be a new position that affects the phenotypic expression of deafness associated 12s rRNA A1555G mutation / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To identify secondary mutations associated with deafness in a Chinese family affected with deafness.</p><p><b>METHODS</b>The family has been subjected to clinical and molecular analyses, in addition with measurement of reactive oxygen species and doubling time after establishment of immortalized lymphocyte cell lines.</p><p><b>RESULTS</b>The results showed that the hearing loss level and audiometric configuration were discrepant among the family members with maternally transmitted hearing loss. The penetrance of hearing loss in this family was respectively 66.7% and 44.4% when aminoglycoside-induced hearing loss was included or excluded. Analysis of whole mitochondrial genome has found 33 variants as previously reported polymorphisms, except for a 12s rRNA A1555G mutation and a tRNA(Thr)T15943C mutation. Haplotype evolutionary tree has verified that this family belonged to East-Asian haplogroup F. 15943 position was located on the T-stem of the tRNA(Thr), which has destroyed the extremely conserved T-A base pair when T changed to C at this position. However, functional experiments indicated that the population doubling time in special galactose and glucose were longer, whilst the level of reactive oxygen species has increased. Compared with the control cell line groups and a family only carrying the 12s rRNA A1555G mutation, all of the three groups belonged to the same haplogroup.</p><p><b>CONCLUSION</b>Mitochondrial tRNA(Thr)T15943C mutation may act as a potential modifying factor and interact with 12s rRNA A1555G mutation, and thereby enhance the penetrance and expression of deafness.</p>

Function study of non-syndromic deafness associated mitochondrial 12S rRNA A839G mutation / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To investigate the correlation between nonsyndromic deafness and mitochondrial 12s rRNA A839G mutation.</p><p><b>METHODS</b>According to the clinical manifestations of mitochondrial DNA sequencing and analysis to find and determine family containing mitochondrial 12s rRNA A839G mutation. Harvested its family members blood and transferred their lymphocytes into lymphoblastoid cell lines, followed by cells cultured, cell doubling experiment, susceptibility testing, cellular oxygen consumption rate experiment, ROS and mitochondrial membrane potential experimental tests were progressed to explore the correlation between the A839G mutation and nonsyndromic deafness.</p><p><b>RESULTS</b>The mitochondrial 12s rRNA A839G mutation pedigrees were determined through the full sequence detections of the Mitochondrial DNA, further phylogenetic analysis showed that 839 point conservative index (CI) up to 78.6%; in RPMI-galactose medium containing A839G gene mutant cell line, the doubling time was significantly longer than the control group, and the difference was significant (P = 0.033). The effect to cell lines containing the A839G mutation of aminoglycoside drugs was not obvious. When compared with the control group, cell lines containing the A839G mutation significantly reduced cellular oxygen consumption rate(P = 0.033); compared with the control group, the ROS levels of cell lines containing the A839G mutation appeared more substantial elevated with significan difference (P < 0.01). The mitochondrial membrane potential of cells of experimental group was significantly reduced than the control group.</p><p><b>CONCLUSION</b>The present study proved that the mitochondria 12s rRNA A839G mutations affect the function of the mitochondrial respiratory chain at the cell level, which might reduce the growth rate of the mutant cell lines, result in hearing.</p>