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Mutations in nuclear genes regulating mitochondrial DNA (mtDNA) replication are associated with mtDNA depletion syndromes. Using whole-genome sequencing, we identified a heterozygous mutation (c.272G>A:p.Arg91Gln) in single-stranded DNA-binding protein 1 (SSBP1), a crucial protein involved in mtDNA replisome. The proband manifested symptoms including sensorineural deafness, congenital cataract, optic atrophy, macular dystrophy, and myopathy. This mutation impeded multimer formation and DNA-binding affinity, leading to reduced efficiency of mtDNA replication, altered mitochondria dynamics, and compromised mitochondrial function. To correct this mutation, we tested two adenine base editor (ABE) variants on patient-derived fibroblasts. One variant, NG-Cas9-based ABE8e (NG-ABE8e), showed higher editing efficacy (≤30%) and enhanced mitochondrial replication and function, despite off-target editing frequencies; however, risks from bystander editing were limited due to silent mutations and off-target sites in non-translated regions. The other variant, NG-Cas9-based ABE8eWQ (NG-ABE8eWQ), had a safer therapeutic profile with very few off-target effects, but this came at the cost of lower editing efficacy (≤10% editing). Despite this, NG-ABE8eWQ-edited cells still restored replication and improved mtDNA copy number, which in turn recovery of compromised mitochondrial function. Taken together, base editing-based gene therapies may be a promising treatment for mitochondrial diseases, including those associated with SSBP1 mutations.
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Branchio-oto-renal (BOR) and branchio-otic (BO) syndromes are characterized by anomalies affecting the ears, often accompanied by hearing loss, as well as abnormalities in the branchial arches and renal system. These syndromes exhibit a broad spectrum of phenotypes and a complex genomic landscape, with significant contributions from the EYA1 gene and the SIX gene family, including SIX1 and SIX5. Due to their diverse phenotypic presentations, which can overlap with other genetic syndromes, molecular genetic confirmation is essential. As sequencing technologies advance, whole-genome sequencing (WGS) is increasingly used in rare disease diagnostics. We explored the genomic landscape of 23 unrelated Korean families with typical or atypical BOR/BO syndrome using a stepwise approach: targeted panel sequencing and exome sequencing (Step 1), multiplex ligation-dependent probe amplification (MLPA) with copy number variation screening (Step 2), and WGS (Step 3). Integrating WGS into our diagnostic pipeline detected structure variations, including cryptic inversion and complex genomic rearrangement, eventually enhancing the diagnostic yield to 91%. Our findings expand the genomic architecture of BOR/BO syndrome and highlight the need for WGS to address the genetic diagnosis of clinically heterogeneous rare diseases.
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Síndrome Branquio Oto Renal , Variaciones en el Número de Copia de ADN , Secuenciación Completa del Genoma , Humanos , Síndrome Branquio Oto Renal/genética , República de Corea , Secuenciación Completa del Genoma/métodos , Femenino , Masculino , Variaciones en el Número de Copia de ADN/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedades Raras/genética , Proteínas Nucleares/genética , Proteínas de Homeodominio/genética , Niño , Proteínas Tirosina Fosfatasas/genética , Preescolar , Adulto , Genómica/métodos , Fenotipo , Linaje , Adolescente , LactanteRESUMEN
The relationship between tinnitus and body composition in specific regions has not been extensively investigated. This study aimed to identify associations between tinnitus and body composition. Individuals with data on physical and otological examination findings, and bioelectrical impedance analysis were included from the ninth Korea National Health and Nutritional Examination Survey. They were divided into a tinnitus group and a non-tinnitus group. Participants with tinnitus were further classified into acute or chronic tinnitus group. The tinnitus group showed significantly higher body fat percentages in each region (arms: P = 0.014; legs: P = 0.029; trunk: P = 0.008; whole body: P = 0.010) and waist circumference (P = 0.007) than the non-tinnitus group, and exhibited lower leg muscle percentage (P = 0.038), total body fluid percentage (P = 0.010), and intracellular fluid percentage (P = 0.009) than the non-tinnitus group in men. Furthermore, men with chronic tinnitus showed a significantly higher trunk fat percentage (P = 0.015) and waist circumference (P = 0.043), and lower intracellular fluid percentage (P = 0.042) than their counterparts without tinnitus. No significant differences in body composition were observed among the groups in the female population. In men, body composition may be associated with tinnitus.
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Composición Corporal , Acúfeno , Humanos , Acúfeno/fisiopatología , Acúfeno/epidemiología , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Adulto , República de Corea/epidemiología , Circunferencia de la Cintura , Impedancia Eléctrica , Anciano , Encuestas NutricionalesRESUMEN
While volatile organic compounds (VOCs) impair various organs, their influence on hearing loss (HL) has not been extensively researched. We aimed to identify the association between VOCs and HL or high-frequency hearing loss (HFHL). We extracted data on age, sex, pure tone audiometry, hypertension, occupational noise exposure, and creatinine-corrected urine VOC metabolite concentrations from the eighth Korea National Health and Nutrition Survey. Among the VOC metabolites, N-acetyl-S-(benzyl)-L-cysteine (BMA, P = 0.004), N-acetyl-S-(phenyl)-L-cysteine (SPMA, P = 0.027), and N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA, P < 0.001) showed associations with HL. Additionally, HFHL exhibited significant associations with BMA (P = 0.005), 3- and 4-methylhippuric acid (3, 4 MHA, P = 0.049), mandelic acid (MA, P = 0.015), SPMA (P < 0.001), N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3-HPMA, P < 0.001), and DHBMA (P < 0.001). After controlling other factors, DHBMA were associated with HL (P = 0.021) and HFHL (P = 0.014) and exhibited a linear association with the mean hearing level (ß = 0.054, P = 0.024) and high-frequency hearing level (ß = 0.045, P = 0.037). Since 1,3-butadiene may act as an ototoxic material, early screening for workers exposed to 1,3-butadiene and reducing exposure to 1,3-butadiene in everyday life may be helpful to prevent further HL.
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Butadienos , Pérdida Auditiva , Compuestos Orgánicos Volátiles , Humanos , Femenino , Masculino , Persona de Mediana Edad , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/etiología , Compuestos Orgánicos Volátiles/orina , Compuestos Orgánicos Volátiles/efectos adversos , República de Corea/epidemiología , Adulto , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Anciano , Encuestas Nutricionales , Audiometría de Tonos PurosRESUMEN
Pathogenic structure variations (SVs) are associated with various types of cancer and rare genetic diseases. Recent studies have used Cas9 nuclease with paired guide RNAs (gRNAs) to generate targeted chromosomal rearrangements, focusing on producing fusion proteins that cause cancer, whereas research on precision genome editing for rectifying SVs is limited. In this study, we identified a novel complex genomic rearrangement (CGR), specifically an EYA1 inversion with a deletion, implicated in branchio-oto-renal/branchio-oto syndrome. To address this, two CRISPR-based approaches were tested. First, we used Cas9 nuclease and paired gRNAs tailored to the patient's genome. The dual CRISPR-Cas9 system induced efficient correction of paracentric inversion in patient-derived fibroblast, and effectively restored the expression of EYA1 mRNA and protein, along with its transcriptional activity required to regulate the target gene expression. Additionally, we used CRISPR activation (CRISPRa), which leads to the upregulation of EYA1 mRNA expression in patient-derived fibroblasts. Moreover, CRISPRa significantly improved EYA1 protein expression and transcriptional activity essential for target gene expression. This suggests that CRISPRa-based gene therapies could offer substantial translational potential for approximately 70% of disease-causing EYA1 variants responsible for haploinsufficiency. Our findings demonstrate the potential of CRISPR-guided genome editing for correcting SVs, including those with EYA1 CGR linked to haploinsufficiency.
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Sensorineural hearing loss (SNHL) is the most common sensory disorder, with a high Mendelian genetic contribution. Considering the genotypic and phenotypic heterogeneity of SNHL, the advent of next-generation sequencing technologies has revolutionized knowledge on its genomic architecture. Nonetheless, the conventional application of panel and exome sequencing in real-world practice is being challenged by the emerging need to explore the diagnostic capability of whole-genome sequencing, which enables the detection of both noncoding and structural variations. Small molecules and gene therapies represent good examples of how breakthroughs in genetic understanding can be translated into targeted therapies for SNHL. For example, targeted small molecules have been used to ameliorate autoinflammatory hearing loss caused by gain-of-function variants of NLRP3 and inner ear proteinopathy with OSBPL2 variants underlying dysfunctional autophagy. Strikingly, the successful outcomes of the first-in-human trial of OTOF gene therapy highlighted its potential in the treatment of various forms of genetic hearing loss. clustered regularly interspaced short palindromic repeats (CRISPR)-based technologies are currently being developed for site-specific genome editing to treat human genetic disorders. These advancements have led to an era of genotype- and mechanism-based precision medicine in SNHL practice.
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Hearing loss affects some nutrient intake. Disabling hearing loss may exacerbate these issues. We aimed to evaluate nutrient intake and assess deficiencies based on functional hearing status. The study included 6907 participants with information on demographic factors, nutrient intake, weight, height, disease status, and hearing level in the eighth Korea National Health and Nutrition Examination Survey, conducted from 2019 to 2021. We categorized the participants into 3 groups based on their functional hearing status: bilateral hearing, unilateral hearing, and disabling hearing loss. The disabling hearing loss group showed lower intake of most major nutrients (P < 0.05), dietary fiber (P < 0.001), and most minerals and vitamins (P < 0.05), with some insufficiencies. The unilateral hearing group showed lower intake only for potassium (P = 0.036) compared to the bilateral hearing group and significantly higher intake of hydration (P = 0.039), dietary fiber (P = 0.039), and calcium (P = 0.009) than the disabling hearing loss group. Nutrient insufficiency in the disabling hearing loss group was more prominent in women, and was partially resolved by using hearing aids. Clinicians and nutritionists should consider undernourishment in these patients, and appropriate interventions for nutrition and hearing aids should be recommended.
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Sordera , Audífonos , Pérdida Auditiva , Humanos , Femenino , Encuestas Nutricionales , Ingestión de Alimentos , Fibras de la Dieta , DietaRESUMEN
Ibuprofen, one of the most commonly prescribed nonsteroidal anti-inflammatory drugs, has not been fully assessed for embryonic toxicity in vertebrates. Here, we systematically assessed the embryotoxicity of ibuprofen in Xenopus laevis at various concentrations during embryogenesis. Embryos were treated with different concentrations of ibuprofen, ranging from 8 to 64 mg/L, at 23 °C for 96 h, and examined daily and evaluated at 72 hpf. Lethal or teratogenic effects were documented. For histological analysis, paraffin embedded embryos were transversely sectioned at a thickness of 10-µm and stained with hematoxylin and eosin. Total RNA was isolated from embryos at stages 6, 12, 22 and 36, and real-time quantitative PCR was performed. Ibuprofen-treated embryos showed delayed or failed dorsal lip formation and its closure at the beginning of gastrulation. This resulted in herniation of the endodermal mass after gastrulation under high concentrations of ibuprofen-treated embryos. Underdeveloped intestines with stage and/or intestinal malrotation, distorted microcephaly, and hypoplastic heart, lungs, and pronephric tubules were observed in ibuprofen-treated embryos. Cephalic, cardiac, and truncal edema were also observed in them. The severity of the deformities was observed in a concentration-dependent manner. The teratogenic index was 2.28. These gross and histological disruptions correlated well with the altered expression of each organ marker gene. In conclusion, ibuprofen induced delayed and disrupted gastrulation in the early developmental stage and multiorgan malformation later in the organogenesis stage of Xenopus laevis embryos.
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Ibuprofeno , Teratógenos , Animales , Xenopus laevis , Ibuprofeno/toxicidad , Desarrollo Embrionario , Antiinflamatorios no Esteroideos/farmacología , Embrión no MamíferoRESUMEN
BACKGROUND: TMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations. METHODS: In this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity. RESULTS: We identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability. CONCLUSIONS: This results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.
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Pérdida Auditiva Sensorineural , Proteínas de la Membrana , Animales , Humanos , Caenorhabditis elegans , Pérdida Auditiva Sensorineural/genética , Membrana Dobles de Lípidos , Proteínas de la Membrana/genética , Estudios RetrospectivosRESUMEN
The ClC-K channels CLCNKA and CLCNKB are crucial for the transepithelial transport processes required for sufficient urinary concentrations and sensory mechanoelectrical transduction in the cochlea. Loss-of-function alleles in these channels are associated with various clinical phenotypes, ranging from hypokalemic alkalosis to sensorineural hearing loss (SNHL) accompanied by severe renal conditions, i.e., Bartter's syndrome. Using a stepwise genetic approach encompassing whole-genome sequencing (WGS), we identified one family with compound heterozygous variants in the ClC-K channels, specifically a truncating variant in CLCNKA in trans with a contiguous deletion of CLCNKA and CLCNKB. Breakpoint PCR and Sanger sequencing elucidated the breakpoint junctions derived from WGS, and allele-specific droplet digital PCR confirmed one copy loss of the CLCNKA_CLCNKB contiguous deletion. The proband that harbors the CLCNKA_CLCNKB variants is characterized by SNHL without hypokalemic alkalosis and renal anomalies, suggesting a distinct phenotype in the ClC-K channels in whom SNHL predominantly occurs. These results expanded genotypes and phenotypes associated with ClC-K channels, including the disease entities associated with non-syndromic hearing loss. Repeated identification of deletions across various extents of CLCNKA_CLCNKB suggests a mutational hotspot allele, highlighting the need for an in-depth analysis of the CLCNKA_CLCNKB intergenic region, especially in undiagnosed SNHL patients with a single hit in CLCNKA.
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Alcalosis , Síndrome de Bartter , Sordera , Pérdida Auditiva Sensorineural , Humanos , Síndrome de Bartter/genética , Canales de Cloruro/genética , Estudios de Asociación Genética , Genotipo , Pérdida Auditiva Sensorineural/genética , MutaciónRESUMEN
When medical genetic syndromes are influenced by allelic hierarchies, mutant alleles have distinct effects on clinical phenotypes. Genotype-phenotype correlations for Usher syndrome type 2 (USH2) suggest that the USH2A gene exhibits an allelic hierarchy. Here, we analyzed the phenotypes and genotypes of 16 South Korean patients with USH2A biallelic variants to investigate an allelic hierarchy from audiological and ophthalmological perspectives. Using whole exome and genome sequencing, 18 mutant alleles, including 4 novel alleles, were identified and implicated in USH2A-related disorders. Truncated alleles were linked to earlier onset of subjective hearing loss and more severe thresholds; biallelic truncated alleles had more severe effects. Truncated alleles were also associated with retinal structure degeneration and severe functional deterioration. However, younger patients (aged < 16 years) did not exhibit overt retinitis pigmentosa even when they had biallelic truncated alleles, suggesting that USH2A-related USH2 can mimic nonsyndromic hearing loss. For truncated alleles, there was a clear correlation between mean hearing threshold and 30-Hz flicker electroretinography implicit time. This study provides the first evidence of an USH2A-related allelic hierarchy among South Korean patients; our data yield valuable insights concerning the natural courses of clinical phenotypes and how genotype-based therapies may be used.
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Síndromes de Usher , Humanos , Síndromes de Usher/genética , Alelos , Fenotipo , República de Corea , Proteínas de la Matriz Extracelular/genética , MutaciónRESUMEN
Hybrid colloidal quantum dot (CQD)/organic architectures are promising candidates for emerging optoelectronic devices having high performance and inexpensive fabrication. For unlocking the potential of CQD/organic hybrid devices, enhancing charge extraction properties at electron transport layer (ETL)/CQD interfaces is crucial. Hence, we carefully adjust the interface properties between the ETL and CQD layer by incorporating an interfacial layer for the ETL (EIL) using several types of cinnamic acid ligands. The EIL having a cascading band offset (ΔEC) between the ETL and CQD layer suppresses the potential barrier and the local charge accumulation at ETL/CQD interfaces, thereby reducing the bimolecular recombination. An optimal EIL effectively expands the depletion region that facilitates charge extraction between the ETL and CQD layer while preventing the formation of shallow traps. Representative devices with an EIL exhibit a maximum power conversion efficiency of 14.01% and retain over 80% of initial performances after 300 h under continuous maximum power point operation.
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POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.
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Pérdida Auditiva Sensorineural , Pérdida Auditiva , Humanos , Proteínas de Homeodominio/genética , Pérdida Auditiva Sensorineural/genética , Pérdida Auditiva/genética , Pérdida Auditiva/metabolismo , Factores de Transcripción/genética , Factor de Transcripción Brn-3C/genética , LinajeRESUMEN
Vaccination is the most effective method for preventing the spread of the influenza virus. Cell-based influenza vaccines have been developed to overcome the disadvantages of egg-based vaccines and their production efficiency has been previously discussed. In this study, we investigated whether treatment with forskolin (FSK), an adenylyl cyclase activator, affected the output of a cell-based influenza vaccine. We found that FSK increased the propagation of three influenza virus subtypes (A/H1N1/California/4/09, A/H3N2/Mississippi/1/85, and B/Shandong/7/97) in Madin-Darby canine kidney (MDCK) cells. Interestingly, FSK suppressed the growth of MDCK cells. This effect could be a result of protein kinase A (PKA)-Src axis activation, which downregulates extracellular signal-regulated kinase (ERK)1/2 activity and delays cell cycle progression from G1 to S. This delay in cell growth might benefit the binding and entry of the influenza virus in the early stages of viral replication. In contrast, FSK dramatically upregulated ERK1/2 activity via the cAMP-PKA-Raf-1 axis at a late stage of viral replication. Thus, increased ERK1/2 activity might contribute to increased viral ribonucleoprotein export and influenza virus propagation. The increase in viral titer induced by FSK could be explained by the action of cAMP in assisting the entry and binding of the influenza virus. Therefore, FSK addition to cell culture systems could help increase the production efficiency of cell-based vaccines against the influenza virus.
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Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza , Gripe Humana , Animales , Perros , Humanos , Células de Riñón Canino Madin Darby , Adenilil Ciclasas , Colforsina/farmacología , Subtipo H3N2 del Virus de la Influenza A , Sistema de Señalización de MAP Quinasas , Gripe Humana/prevención & controlRESUMEN
BACKGROUND: The cochlea contains a robust biological clock associated with auditory function, exhibiting diurnal sensitivity to noise or ototoxicity. OBJECTIVES: We examined the relationship between disrupted circadian rhythm and altered expression of circadian clock genes in patients with sudden sensorineural hearing loss (SSNHL) and explored whether the circadian clock genes serve as prognostic biomarkers. MATERIAL AND METHODS: Twelve patients with SSNHL were enrolled study group. Twelve people with normal hearing were enrolled voluntarily for comparison. Audiological evaluation was performed to evaluate hearing thresholds. Korean version of the Pittsburgh Sleep Quality Index Questionnaire was performed to evaluate sleep quality and patterns. Circadian clock genes including for PERI, PER2, PER3, CRYI, CRY2, CLOCK, ARNTL, CSNKIE, and TIMELESS expression in blood were evaluated using real-time quantitative PCR method. RESULTS: Compared with healthy controls without hearing loss, most of the circadian clock genes were markedly downregulated, coupled with low sleep quality and disturbing patterns, in patients with SSNHL. Intriguingly, a weak correlation between hearing improvement following steroid treatment and altered levels of circadian clock genes was observed. CONCLUSIONS AND SIGNIFICANCE: This study provides an additional basis for the relevance of disrupted circadian rhythm to SSNHL and suggests a possible prognostic biomarker for SSNHL treatment.
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Relojes Circadianos , Sordera , Pérdida Auditiva Sensorineural , Trastornos del Sueño-Vigilia , Humanos , Relojes Circadianos/genética , Pérdida Auditiva Sensorineural/genética , Audición , Trastornos del Sueño-Vigilia/genética , SueñoRESUMEN
Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype-phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five SIX1 heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with SIX1 variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with SIX1 variants, compared to 15 BOR/BO syndrome families with EYA1 variants. All SIX1 variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of SIX1 variants in South Korea, expanding the genotypic and phenotypic spectrum of SIX1 variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of SIX1 variants according to the EYA1-SIX1-DNA complex theory.
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Síndrome Branquio Oto Renal , Sordera , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas Tirosina Fosfatasas/genética , Mutación , Linaje , Síndrome Branquio Oto Renal/genética , Fenotipo , República de Corea , ADN/genética , Proteínas de Homeodominio/genéticaRESUMEN
Lead sulfide (PbS) colloidal quantum dots (CQDs) are promising materials for next-generation flexible solar cells because of near-infrared absorption, facile bandgap tunability, and superior air stability. However, CQD devices still lack enough flexibility to be applied to wearable devices owing to the poor mechanical properties of CQD films. In this study, a facile approach is proposed to improve the mechanical stability of CQDs solar cells without compromising the high power conversion efficiency (PCE) of the devices. (3-aminopropyl)triethoxysilane (APTS) is introduced on CQD films to strengthen the dot-to-dot bonding via QD-siloxane anchoring, and as a result, crack pattern analysis reveals that the treated devices become robust to mechanical stress. The device maintains 88% of the initial PCE under 12 000 cycles at a bending radius of 8.3 mm. In addition, APTS forms a dipole layer on CQD films, which improves the open circuit voltage (VOC ) of the device, achieving a PCE of 11.04%, one of the highest PCEs in flexible PbS CQD solar cells.
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BACKGROUND: Bell's palsy is an idiopathic facial palsy with an unknown cause, and 75% of patients heal spontaneously. However, the other 25% of patients continue experiencing mild or severe disabilities, resulting in a reduced quality of life. Currently, various treatment methods have been developed to treat this disease. However, there is controversy regarding their effectiveness, and new alternative treatments are needed. CASE SUMMARY: The patient suffered from left-sided facial paralysis due to Bell's palsy for 7 years. The patient received an uncultured umbilical cord-derived mesenchymal stem cell transplant eight times for treatment. After follow-up for 32 mo, the paralysis was cured, and there was no recurrence. CONCLUSION: Uncultured umbilical cord-derived mesenchymal stem cell transplantation may be a potential treatment for patients with Bell's palsy who do not spontaneously recover.
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OBJECTIVES: To explore the phenotypes and genotypes of patients with branchio-oto-renal (BOR) and branchio-otic (BO) syndrome, and to analyze the middle ear surgery outcomes qualitatively and quantitatively, proposing a factor usefully prognostic of surgical outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. PATIENTS: Eighteen patients with BOR/BO syndrome in 12 unrelated Korean families. INTERVENTION: Middle ear surgery, including either stapes surgery or ossicular reconstruction. MAIN OUTCOME MEASURE: Clinical phenotypes, genotypes, and middle ear surgery outcomes. RESULTS: Eight probands (66.7%) were confirmed genetically; the condition segregated as a dominant or de novo trait. Six EYA1 heterozygous variants were identified by exome sequencing and multiplex ligation-dependent probe amplification. All variants were pathogenic or likely pathogenic based on the ACMG/AMP guidelines. Two novel EYA1 frameshift variants (p.His373Phefs*4 and p.Gln543Asnfs*90) truncating a highly conserved C-terminal Eya domain were identified, expanding the genotypic spectrum of EYA1 in BOR/BO syndrome. Remarkably, middle ear surgery was individualized to ensure optimal audiological outcomes and afforded significant audiological improvements, especially in BOR/BO patients without enlarged vestibular aqueducts (EVAs). A significant difference in air-bone gap closure after middle ear surgery was noted between the two groups even after adjusting for confounders: -20.5 dB in ears without EVAs (improvement) but 0.8 dB in ears with EVAs (no change or deterioration). Furthermore, the success rate was significantly associated with the absence of EVA. CONCLUSIONS: The results of this study were against the notion that middle ear surgery is always contraindicated in patients with BOR/BO syndrome, and an EVA could be a negative prognostic indicator of middle ear surgery in BOR/BO patients. This may aid to determine the strategy of audiological rehabilitation in patients with BOR/BO syndrome.
Asunto(s)
Síndrome Branquio Oto Renal , Humanos , Síndrome Branquio Oto Renal/genética , Síndrome Branquio Oto Renal/cirugía , Proteínas Tirosina Fosfatasas/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Centros de Atención Terciaria , Estudios Retrospectivos , Oído Medio/cirugía , Biología Molecular , LinajeRESUMEN
BACKGROUND: Wolfram syndrome type 1 gene (WFS1), which encodes a transmembrane structural protein (wolframin), is essential for several biological processes, including proper inner ear function. Unlike the recessively inherited Wolfram syndrome, WFS1 heterozygous variants cause DFNA6/14/38 and wolfram-like syndrome, characterized by autosomal dominant nonsyndromic hearing loss, optic atrophy, and diabetes mellitus. Here, we identified two WFS1 heterozygous variants in three DFNA6/14/38 families using exome sequencing. We reveal the pathogenicity of the WFS1 variants based on three-dimensional (3D) modeling and structural analysis. Furthermore, we present cochlear implantation (CI) outcomes in WFS1-associated DFNA6/14/38 and suggest a genotype-phenotype correlation based on our results and a systematic review. METHODS: We performed molecular genetic test and evaluated clinical phenotypes of three WFS1-associated DFNA6/14/38 families. A putative WFS1-NCS1 interaction model was generated, and the impacts of WFS1 variants on stability were predicted by comparing intramolecular interactions. A total of 62 WFS1 variants associated with DFNA6/14/38 were included in a systematic review. RESULTS: One variant is a known mutational hotspot variant in the endoplasmic reticulum (ER)-luminal domain WFS1(NM_006005.3) (c.2051 C > T:p.Ala684Val), and the other is a novel frameshift variant in transmembrane domain 6 (c.1544_1545insA:p.Phe515LeufsTer28). The two variants were pathogenic, based on the ACMG/AMP guidelines. Three-dimensional modeling and structural analysis show that non-polar, hydrophobic substitution of Ala684 (p.Ala684Val) destabilizes the alpha helix and contributes to the loss of WFS1-NCS1 interaction. Also, the p.Phe515LeufsTer28 variant truncates transmembrane domain 7-9 and the ER-luminal domain, possibly impairing membrane localization and C-terminal signal transduction. The systematic review demonstrates favorable outcomes of CI. Remarkably, p.Ala684Val in WFS1 is associated with early-onset severe-to-profound deafness, revealing a strong candidate variant for CI. CONCLUSIONS: We expanded the genotypic spectrum of WFS1 heterozygous variants underlying DFNA6/14/38 and revealed the pathogenicity of mutant WFS1, providing a theoretical basis for WFS1-NCS1 interactions. We presented a range of phenotypic traits for WFS1 heterozygous variants and demonstrated favorable functional CI outcomes, proposing p.Ala684Val a strong potential marker for CI candidates.