We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, the average age at onset of deafness has changed from 55 years (generation II) to 10 years (generation IV). Clinical data reveal that the administration of aminoglycosides can induce or worsen deafness in matrilineal relatives. The age at the time of drug administration appears to be correlated with the severity of hearing loss experienced by affected individuals. Sequence analysis of mitochondrial DNA in this pedigree identified a homoplasmic C-to-T transition at position 1494 (C1494T) in the 12S rRNA gene. The C1494T mutation is expected to form a novel U1494-1555A base pair, which is in the same position as the C1494-1555G pair created by the deafness-associated A1555G mutation, at the highly conserved A site of 12S rRNA. Exposure to a high concentration of paromomycin or neomycin caused a variable but significant average increase in doubling time in lymphoblastoid cell lines derived from four symptomatic and two asymptomatic individuals in this family carrying the C1494T mutation when compared to four control cell lines. Furthermore, a significant decrease in the rate of total oxygen consumption was observed in the mutant cell lines. Thus, our data strongly support the idea that the A site of mitochondrial 12S rRNA is the primary target for aminoglycoside-induced deafness. These results also strongly suggest that the nuclear background plays a role in the aminoglycoside ototoxicity and in the development of the deafness phenotype associated with the C1494T mutation in the mitochondrial 12S rRNA gene.

Background: Mutations in GJB2 are the most common molecular defects responsible for autosomal recessive nonsyndromic hearing impairment (NSHI). The mutation spectra of this gene vary among different ethnic groups.

Background: Every year, 30,000 babies are born with congenital hearing impairment in China. The molecular etiology of hearing impairment in the Chinese population has not been investigated thoroughly. To provide appropriate genetic testing and counseling to families, we performed a comprehensive investigation of the molecular etiology of nonsyndromic deafness in two typical areas from northern and southern China.

The NLRP3 (nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3) inflammasome-mediated inflammatory responses are critically involved in the progression of atherosclerosis (AS), which is the essential cause for cardiovascular diseases. Melatonin has anti-inflammatory properties. However, little is known about the potential effects of melatonin in the pathological process of AS. Herein, we demonstrate that melatonin suppressed prolonged NLRP3 inflammasome activation in atherosclerotic lesions by reactive oxygen species (ROS) scavenging via mitophagy in macrophages. The atherosclerotic mouse model was induced with a high-fat diet using ApoE−/− mice. Melatonin treatment markedly attenuated AS plaque size and vulnerability. Furthermore, melatonin decreased NLRP3 inflammasome activation and the consequent IL-1β secretion within atherosclerotic lesions. Despite the unchanged protein expression, the silent information regulator 3 (Sirt3) activity was elevated in the atherosclerotic lesions in melatonin-treated mice. In ox-LDL-treated macrophages, melatonin attenuated the NLRP3 inflammasome activation and the inflammatory factors secretion, while this protective effect was abolished by either Sirt3 silence or autophagy inhibitor 3-MA. Mitochondrial ROS (mitoROS), which was a recognized inducer for NLRP3 inflammasome, was attenuated by melatonin through the induction of mitophagy. Both Sirt3-siRNA and autophagy inhibitor 3-MA partially abolished the beneficial effects of melatonin on mitoROS clearance and NLRP3 inflammasome activation, indicating the crucial role of Sirt3-mediated mitophagy. Furthermore, we demonstrated that melatonin protected against AS via the Sirt3/FOXO3a/Parkin signaling pathway. In conclusion, the current study demonstrated that melatonin prevented atherosclerotic progression, at least in part, via inducing mitophagy and attenuating NLRP3 inflammasome activation, which was mediated by the Sirt3/FOXO3a/Parkin signaling pathway. Collectively, our study provides insight into melatonin as a new target for therapeutic intervention for AS.