Abstract: Recently, researchers from the General Hospital of the People’s Liberation Army (PLA), Emory University, UW Genetics and Fudan University published their latest research results on dominant deafness nail dystrophy syndrome in the prestigious journal “Cell Research” in the form of “Letter to the Editor”. Recently, researchers from the General Hospital of the People’s Liberation Army (PLA), Emory University, UW-Gene and Fudan University published a new study on dominant deafness nail dystrophy syndrome in the prestigious journal Cell Research in the form of a Letter to the Editor. The article is entitled “De novo mutation in ATP6V1B2 impairs lysosome acidification and causes dominant deafness- onychodystrophy syndrome. onychodystrophy syndrome”. The study used exome sequencing to identify a de novo mutation in the ATP6V1B2 gene as the cause of this inherited deafness. The corresponding authors of the report are Prof. Park Dai of PLA General Hospital and Prof. Xi Lin of Emory University School of Medicine, respectively. He specializes in the surgical treatment of chronic otitis media otosclerosis, severe sensorineural deafness, and lateral skull base tumors, and specializes in cochlear implantation, stapes surgery, and other hearing enhancement procedures. He is the first specialist in China to perform cochlear soft electrode implantation, acoustic bridge implantation, minimally invasive electrode implantation and minimally invasive cochlear surgery. Dominant deafness-onychodystrophy syndrome (DDOD syndrome; MIM 124480) is characterized by congenital sensorineural deafness with dystrophy or absence of nails. malnutrition, osteodystrophy, mental retardation, and seizures; MIM 220500) stand out from each other in that DOORS has aspects of mental retardation and seizures. Recently, the TBC1D24 mutation has been identified as a cause of DOORS syndrome. To date, six families with DDOD syndrome from different ethnic populations have been reported. However, the molecular etiology of DDOD remains unclear. The team collected three Chinese DDOD pedigrees in the past two years. The primary patients exhibited the same phenotype, including severe congenital sensorineural deafness, absence of nails, and hypoplasia of the middle phalanges of the fifth finger. No inner ear malformation or intellectual disability was demonstrated. All three patients underwent unilateral cochlear implantation at ages 2.5, 2, and 18 years, respectively. successful speech rehabilitation in DDOD patients further confirmed normal psychological development. The researchers performed whole-exome sequencing of Spectrum 1 and 2, including the primary patients and their parents. Six variant genes were found to be shared between the two primary patients. Then, 14 variants of these six shared genes were examined by Sanger sequencing, and combined with multiple analyses, ATP6V1B2 was identified as a potential gene associated with DDOD. This result was further confirmed by Sanger sequencing of other DDOD pedigrees. The researchers then used restriction endonuclease analysis to perform molecular epidemiological analysis in 1053 ethnically matched normal controls. The mutation was not detected in the population with normal hearing. Although this de novo mutation, has recently been shown to play a major role in human disorders of intellectual disability (e.g., Dravet syndrome, Kabuki syndrome, and Schinzel-Giedion syndrome), it is extremely rare to find the same de novo mutation in these three unrelated DDOD patients. ATP6V1B2 encodes a component of the vesicular ATPase (V-ATPase), a multisubunit enzyme that mediates the acidification of organelles in eukaryotic cells. To explore the function of ATP6V1B2 in the cochlea, researchers prepared a cochlea-specific Atp6v1b2 knockout mouse model using morpholine-substituted zwitterion (MO). Atp6v1b2 MO was microinjected into the base of the cochlea three days after the mice were born. The researchers found that the auditory sensitivity of the mice was not affected by this injection procedure. western blot analysis showed that Atp6v1b2 levels in spiral ganglion neurons decreased significantly 7 days after injection, and 21 days after injection, Atp6v1b2 levels in the spiral apparatus decreased significantly. Subsequently, the researchers assessed the pathogenicity of ATP6V1B2 and found that the ATP6V1B2 c.1516 C>T mutation is a single underdose (haploinsufficient) mutation. In conclusion, this study used whole-exome sequencing in three independently identified patients with DDOD syndrome and identified a de novo mutation (c.1516 C>T (p.Arg506X)) in ATP6V1B2 as the cause of DDOD syndrome. Molecular epidemiological analysis showed that the mutation was not present in 1053 racially matched normal hearing controls. Using a mouse model, it was found that Atp6v1b2 deficiency can lead to severe sensorineural deafness. In vitro pathogenic evaluation revealed that ATP6V1B2 p.Arg506X is a single underdose mutation that causes abnormal acidification of the lysosome. These findings provide a molecular basis for the genetic diagnosis of DDOD, as well as for future therapeutic interventions.