The co-occurrence of sensorineural hearing loss and male infertility has been reported in several instances, suggesting potential shared genetic underpinnings. One such example is the contiguous gene deletion of CATSPER2 and STRC genes, previously associated with deafness-infertility syndrome (DIS) in males. Fifteen males with both hearing loss and infertility from southern India after exclusion for the DIS contiguous gene deletion and the FOXI1 gene mutations are subjected to exome sequencing. This resolves the genetic etiology in four probands for both the phenotypes; In the remaining 11 probands, two each conclusively accounted for deafness and male infertility etiologies. Genetic heterogeneity is well reflected in both phenotypes. Four recessive (TRIOBP, SLC26A4, GJB2, COL4A3) and one dominant (SOX10) for the deafness; six recessive genes (LRGUK, DNAH9, ARMC4, DNAH2, RSPH6A, and ACE) for male infertility can be conclusively ascribed. LRGUK and RSPH6A genes are implicated earlier only in mice models, while the ARMC4 gene is implicated in chronic destructive airway diseases due to primary ciliary dyskinesia. This study would be the first to document the role of these genes in the male infertility phenotype in humans. The result suggests that deafness and infertility are independent events and do not segregate together among the probands.

OBJECTIVE: The aim of this study was to explore the functional consequences of two common variants, p.V37I and c.299-300delAT, in the hearing loss-associated gene GJB2.
METHODS: Connexin 26 expression and gap junctional permeability were studied in HEK 293T cells transfected with plasmids expressing GJB2 wild-type, p.V37I, or c.299-300delAT CX26 proteins tagged with fluorescent markers. Functional analyses of various GJB2 haplotypes were conducted to thoroughly evaluate alterations in ionic and small-molecule coupling.
RESULTS: The p.V37I protein was localized at the plasma membrane, but it failed to effectively transport intercellular propidium iodide or Ca2+ efficiently, indicating an impairment in both biochemical and ionic coupling. The presence of GJB2 p.V37I seemed to increase the cells\' sensitivity to H2O2 treatment. In contrast, the known variant c.299-300delAT protein was not transported to the cell membrane and was unable to form gap junctions, remaining confined to the cytoplasm. Both ionic and biochemical coupling were defective in cells transfected with c.299-300delAT.
CONCLUSIONS: The p.V37I and c.299-300delAT GJB2 mutations resulted in deficient gap junction-mediated coupling. Additionally, environmental factors could influence the functional outcomes of the GJB2 p.V37I mutation. These findings could pave the way for the development of molecular therapies targeting GJB2 mutations to treat hearing loss.

BACKGROUND: Mutations in the GJB2 gene, which encodes the protein connexin 26 and is involved in inner ear homeostasis, are identified in approximately 50% of patients with autosomal recessive nonsyndromic hearing loss, making it one of the primary causes of prelingual nonsyndromic hearing loss in various populations. The 35delG mutation, one of the most common mutations of the GJB2 gene, usually causes prelingual, bilateral mild to profound, nonprogressive sensorineural hearing loss.
METHODS: We present an unusual case of an 18-year-old Turkish female with heterozygous 35delG mutation and postlingual, profound-sloping, progressive and fluctuating unilateral sensorineural hearing loss. The phenotype is different from the usual findings.
CONCLUSIONS: The 35delG mutation causing hearing loss may not always be reflected in the phenotype as expected and therefore may have different audiologic manifestations.

OBJECTIVE: The crystal structure of the six protomers of gap junction protein beta 2 (GJB2) enables prediction of the effect(s) of an amino acid substitution, thereby facilitating investigation of molecular pathogenesis of missense variants of GJB2. This study mainly focused on R143W variant that causes hearing loss, and investigated the relationship between amino acid substitution and 3-D structural changes in GJB2.
METHODS: Patients with nonsyndromic hearing loss who appeared to have two GJB2 pathogenic variants, including the R143W variant, were investigated. Because the X-ray crystal structure of the six protomers of the GJB2 protein is known, R143W and structurally related variants of GJB2 were modeled using this crystal structure as a template. The wild-type crystal structure and the variant computer-aided model were observed and the differences in molecular interactions within the two were analyzed.
RESULTS: The predicted structure demonstrated that the hydrogen bond between R143 and N206 was important for the stability of the protomer structure. From this prediction, R143W related N206S and N206T variants showed loss of the hydrogen bond.
CONCLUSIONS: Investigation of the genotypes and clinical data in patients carrying the R143W variant on an allele indicated that severity of hearing loss depends largely on the levels of dysfunction of the pathogenic variant on the allele, whereas a patient with the homozygous R143W variant demonstrated profound hearing loss. We concluded that these hearing impairments may be due to destabilization of the protomer structure of GJB2 caused by the R143W variant.

In this study, we report a case of bilateral mild hearing loss and keratoderma caused by a gap junction beta-2 (GJB2) variant. The proband was a nine-year-old Japanese boy with bilateral mild hearing loss at birth. The proband\'s father, sister, paternal aunt, and cousins had mild sensorineural hearing loss. Further evaluation revealed keratoderma on the feet of the proband, father, sister, paternal aunt, and cousins. We identified a heterozygous c.250G>A (p.Val84Met) variant in GJB2 as the cause of the autosomal dominant syndromic hearing loss with the skin disorder in this Japanese family and delineated the pathological significance of the variant. The Val84Met variant in GJB2 contributes to the autosomal dominant form of syndromic hearing loss with keratoderma.

UNASSIGNED: Hearing loss is a common sensorineural dysfunction with a high incidence in China. Although genetic factors are important causes of hearing loss, hearing-related gene detection has not been widely adopted in China.
UNASSIGNED: Establishing a rapid and efficient method to simultaneously detect hotspot hearing loss gene mutations.
UNASSIGNED: A reverse dot blot assay combined with a flow-through hybridization technique was developed for the simultaneous detection of 13 hotspot mutations of 4 hearing loss-related genes including GJB2, GJB3, SLC26A4, and the mitochondrial gene MT-RNR1. This method involved PCR amplification systems and a hybridization platform.
UNASSIGNED: The technique can detect 13 hotspot mutations of 4 hearing loss-related genes. And a total of 213 blood samples were used to evaluate the availability of this method.
UNASSIGNED: Our reverse dot blot assay was a simple, rapid, accurate, and cost-effective method to identify hotspot mutations of 4 hearing loss-related genes in a Chinese population.

Objective:To elucidate the correlation between the GJB2 gene and auditory neuropathy, aiming to provide valuable insights for genetic counseling of affected individuals and their families. Methods:The general information, audiological data（including pure tone audiometry, distorted otoacoustic emission, auditory brainstem response, electrocochlography）, imaging data and genetic test data of 117 auditory neuropathy patients, and the patients with GJB2 gene mutation were screened out for the correlation analysis of auditory neuropathy. Results:Total of 16 patients were found to have GJB2 gene mutations, all of which were pathogenic or likely pathogenic.was Among them, one patient had compound heterozygous variants GJB2[c. 427C>T][c. 358_360del], exhibiting total deafness. One was GJB2[c. 299_300delAT][c. 35_36insG]compound heterozygous variants, the audiological findings were severe hearing loss.The remaining 14 patients with GJB2 gene variants exhibited typical auditory neuropathy. Conclusion:In this study, the relationship between GJB2 gene and auditory neuropathy was preliminarily analyzed,and explained the possible pathogenic mechanism of GJB2 gene variants that may be related to auditory neuropathy.
目的：探究GJB2基因与听神经病之间的关系，为此类患者及家庭的遗传咨询提供参考。 方法：对117例听神经病患者的基本信息、听力学资料（包括纯音测听、畸变耳声发射、听性脑干反应、耳蜗电图）、影像学资料、遗传学检测等数据进行收集，并筛选出携带GJB2基因变异的患者对其进行听神经病相关分析。 结果：共计16例患者检出GJB2基因变异，变异位点致病性均为致病的或可能致病的，其中1例为GJB2[c.427C>T][c.358_360del]复合杂合变异，听力学表现为全聋，1例为GJB2[c.299_300delAT][c.35_36insG]复合杂合变异，听力学表现为重度听力损失，其余14例携带GJB2基因变异患者听力学表型均为典型听神经病。 结论：本研究初步分析了GJB2基因与听神经病的相关性，并阐述了GJB2基因变异可能与听神经病表型相关的致病机制。.

Background: Preconception or prenatal carrier screening plays an important role in reproductive decision-making, but current research on hereditary deafness is limited. This study aimed to investigate the carrier frequencies of common deafness genes in the Chinese population who underwent carrier screening and to follow up on pregnancy outcomes in high-chance couples. Methods: Individual females or couples in preconception or early pregnancy were recruited from two hospitals in China. Carrier screening for common deafness genes in the Chinese population, including the GJB2 and SLC26A4 genes, was performed using next-generation sequencing technology. Genetic counseling was provided to subjects before and after testing. Results: Of the 9,993 subjects screened, the carrier rate was 2.86% for the GJB2 gene and 2.63% for the SLC26A4 gene. The variant with the highest carrier frequency in GJB2 was c.235delC (1.89%), and c.919-2A>G (1.08%) in SLC26A4. Of the six high-chance couples, four made alternative reproductive decisions (three with prenatal diagnosis and one with preimplantation genetic testing), with consequent termination of the birth of two affected fetuses. Conclusion: These findings confirmed the clinical utility of preconception or prenatal carrier screening for hereditary deafness.

UNASSIGNED: Cell death is a key regulatory process in organisms and its study has become increasingly important in the field of cancer. While prior research has primarily centered on the individual pathways of cell death in cancer, there has been a lack of comprehensive investigation into the synergistic effects of multiple cell death pathways.
UNASSIGNED: Genes related to autophagy, apoptosis, necroptosis, pyroptosis, and cuproptosis was selected, and patients\' data was collected from The Cancer Genome Atlas (TCGA)project. Cell death features were identified using principal component analysis and combined to create a composite score. A scalable prediction model was then created using LASSO regression after a thorough assessment of the composite scores. The model was subsequently validated across multiple external datasets to establish its robustness and reliability.
UNASSIGNED: The cell death features effectively represented the gene expression patterns in the samples. The composite score well predicted prognosis, clinical stage, mutation, tumor microenvironment, and immunotherapy effectiveness. The model built on composite scores accurately predicted prognosis and immunotherapy effectiveness across multiple datasets. GJB2 was identified as a potential biomarker.
UNASSIGNED: Models based on multiple cell death pathways have significant predictive power for prognosis and immunotherapy effectiveness in lung adenocarcinoma. This highlights the synergistic role of multiple cell death pathways in cancer development and offers a new perspective for cancer research.

We aimed to investigate whether the degree of hearing loss with GJB2 mutations could be predicted by distinguishing between truncating and non-truncating mutations and whether the genotype could predict the hearing loss level. Additionally, we examined the progression of hearing loss in individuals monitored for over 2 years for an average of 6.9 years. The proportion of truncating mutations was higher in patients with profound and severe hearing loss, but it was not accurate enough to predict the degree of hearing loss. Via genotype analysis, mutations of the p.Arg143Trp variants were associated with profound hearing loss, while mutations of the p.Leu79Cysfs*3 allele exhibited a wide range of hearing loss, suggesting that specific genotypes can predict the hearing loss level. Notably, there were only three cases of progression in four ears, all of which involved the p.Leu79Cysfs*3 mutation. Over the long-term follow-up, 4000 Hz was significant, and there was a trend of progression at 250 Hz, suggesting that close monitoring at these frequencies during follow-up may be crucial to confirm progression. The progression of hearing loss was observed in moderate or severe hearing loss cases at the time of the initial diagnosis, emphasizing that children with this level of hearing loss need regular follow-ups.