Unveiling a novel GJB2 dominant K22T mutation in a Chinese family with hearing loss.

Hearing loss constitutes one of the most prevalent conditions within the field of otolaryngology. Recent investigations have revealed that mutations in deafness-associated genes, including point mutations and variations in DNA sequences, can cause hearing impairments. With the ethology of deafness remaining unclear for a substantial portion of the affected population, further screenings for pathogenic mutations are imperative to unveil the underlying mechanisms. On this study, by using next-generation sequencing, we examine 129 commonly implicated deafness-related genes in a Chinese family with hearing loss, revealing a novel heterozygous dominant mutation in the GJB2 gene (GJB2: c.65T>G: p. Lys22Thr). This mutation consistently occurs in affected family members but is not detected in unaffected individuals, strongly suggesting its causative role in hearing loss. Structural analysis indicates potential disruption to the Cx26 gap junction channel's hydrogen bond and electrostatic interactions, aligning with predictions from the PolyPhen and SIFT algorithms. In conclusion, our study provides conclusive evidence that the identified heterozygous GJB2 mutation (GJB2: c.65T>G: p. Lys22Thr), specifically the K22T alteration, is the primary determinant of the family's deafness. This contribution enhances our understanding of the interplay between common deafness-associated genes and hearing loss, offering valuable insights for diagnostic guidance and the formulation of therapeutic strategies for this condition.

Directed Asymmetric Nickel-Catalyzed Reductive 1,2-Diarylation of Electronically Unactivated Alkenes.

Transition-metal catalyzed intermolecular 1,2-diarylation of electronically unactivated alkenes has emerged as an extensive research topic in organic synthesis. However, most examples are mainly limited to terminal alkenes. Furthermore, transition-metal catalyzed asymmetric 1,2-diarylation of unactivated alkenes still remains unsolved and is a formidable challenge. Herein, we describe a highly efficient directed nickel-catalyzed reductive 1,2-diarylation of unactivated internal alkenes with high diastereoselectivities. More importantly, our further effort towards enantioselective 1,2-diarylation of the unactivated terminal and challenging internal alkenes is achieved, furnishing various polyarylalkanes featuring benzylic stereocenters in high yields and with good to high enantioselectivities and high diastereoselectivities. Interestingly, the generation of cationic Ni-catalyst by adding alkali metal fluoride is the key to increased efficiency of this enantioselective reaction.

Novel cis compound heterozygous variants in MYO6 causes early onset of non-syndromic hearing loss in a Chinese family.

Background: Mutations in the MYO6 gene have been associated with both autosomal dominant non-syndromic hearing loss (ADNSHL) and autosomal recessive non-syndromic hearing loss (ARNSHL), with a cumulative identification of 125 pathogenic variants. To investigate the underlying genetic factor within a Chinese family affected with heriditary hearing loss, prompted the utilization of high-throughput sequencing. Method: A detailed clinical investigation was performed. Genetic testing was performed by using target panel sequencing, and Sanger sequencing. Targeted sequencing identified the variants and Sanger sequencing was employed to validate segregation of the identified variants within family. Additionally, bioinformatics analysis was performed to strengthen our findings. Results: Clinical investigation revealed the family members were affected by progressive and sensorineural hearing loss with an onset around 8-10 years old. Furthermore, genetic testing identified novel MYO6 variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn], positioned in a cis pattern, as plausible pathogenic contributors to early-onset hearing loss characterized by a severe and progressive course. Moreover, bioinformatics analysis showd disruptin in hydrogen bonding of mutant amino acids with interactive amino acids. Conclusion: Our research uncovered a relationship between mutations in the MYO6 gene and non-syndromic hearing loss. We identified two variants, c.[2377T>G; 2382G>T] p.[Trp793Gly; Lys794Asn] in MYO6 as strong candidates responsible for the observed progressive hereditary hearing loss. This study not only adds to our knowledge about hearing problems related to MYO6 but also reveals the presence of monogenic compound heterozygosity. Our study will provide a new sight for genetic diagnosis in such patients and their management for future use.

Nickel-Catalyzed Enantioselective Coupling of Acid Chlorides with α-Bromobenzoates: An Asymmetric Acyloin Synthesis.

The reaction of common acyl-metal species (acyl anion) with aldehydes to furnish acyloins has received much less attention and specifically was restricted to using preformed stoichiometric acyl-metal reagents. Moreover, the (catalytic) enantioselective variants remain unexplored, and the asymmetric synthesis of chiral acyloins has met significant challenges in organic synthesis. Here, we uncover the highly enantioselective coupling of acid chlorides with α-bromobenzoates by nickel catalysis for producing enantioenriched protected α-hydroxy ketones (acyloins, >60 examples) with high enantioselectivities (up to 99% ee). The successful execution of this enantioselective coupling protocol enables the formation of a key ketyl radical from α-bromoalkyl benzoate in situ generated from corresponding aldehyde and acyl bromide, which finally is captured by chiral acyl-Ni species catalytically in situ formed from acyl chlorides, thus avoiding the use of preformed acyl-metal reagents. The synthetic utility of this chemistry is demonstrated in the downstream synthetic elaboration toward a diverse set of synthetically valuable chiral building blocks and biologically active compounds.

Clinical Phenotype and Genetic Features of a Pair of Chinese Twins with Kearns-Sayre Syndrome.

Kearns-Sayre Syndrome (KSS) is a severe mitochondrial disorder involving the central nervous system, eyes, ears, skeletal muscles, and heart. The mitochondrial DNA (mtDNA) rearrangements, especially the deletions, are present in almost all KSS patients and considered as the disease-causing factor. However, the size and position of mtDNA deletions are distinct in different individuals. In this study, we report the case of a pair of Chinese twins with KSS. The twin patients revealed typical KSS clinical symptoms, including heart block, bilateral sensorineural hearing loss, progressive external ophthalmoplegia, exercise intolerance, proximal limb weakness, and endocrine disorders. Using long-range polymerase chain reactions (long-range PCR) and next-generation sequencing (NGS), the genetic features of the twin patients were investigated. A large 6600 bp mtDNA deletion, ranging from position 8702 to 15,302, was detected in both patients. To our knowledge, this kind of mtDNA deletion has never been described previously. Our study enriched the mutation spectrum of KSS and showed that NGS is a powerful tool for detecting mtDNA large variants.

Differences in the regeneration traits of Potamogeton crispus turions from macrophyte- and phytoplankton-dominated lakes.

Potamogeton crispus is widely used in submerged macrophyte restoration in China. Turions are an important means of reproduction in this species. To compare the regeneration abilities of P. crispus turions in macrophyte- and phytoplankton-dominated lakes, we collected P. crispus turions from a macrophyte-dominated lake (Liangzi Lake) and a phytoplankton-dominated lake (Taihu Lake). Both lakes are important lakes in the middle and lower reaches of the Yangtze River in China. Our field survey revealed that the turions from the phytoplankton-dominated lake had smaller sizes and higher concentrations of total nitrogen (TN) and total phosphorus (TP) than did those from the macrophyte-dominated lake. Rapid sprouting of the turions from the phytoplankton-dominated lake in 32 days was observed under experimental conditions, although the sprout sizes (heights and biomass) were smaller than those from the macrophyte-dominated lake. Compared with sprouted turions from macrophyte-dominated lake, the sprouted turions from the phytoplankton-dominated lake accumulated higher soluble sugar (SS) but lower starch and free amino acid (FAA) concentrations. A 12-day interval sprout removal treatment significantly stimulated the re-sprouting of turions from both lakes, but scale-leaf-removal treatments had no effect. This study provides evidence that the regeneration strategies of P. crispus turions differ in macrophyte- and phytoplankton-dominated lakes.

Combined examination of sequence and copy number variations in human deafness genes improves diagnosis for cases of genetic deafness.

BACKGROUND: Copy number variations (CNVs) are the major type of structural variation in the human genome, and are more common than DNA sequence variations in populations. CNVs are important factors for human genetic and phenotypic diversity. Many CNVs have been associated with either resistance to diseases or identified as the cause of diseases. Currently little is known about the role of CNVs in causing deafness. CNVs are currently not analyzed by conventional genetic analysis methods to study deafness. Here we detected both DNA sequence variations and CNVs affecting 80 genes known to be required for normal hearing. METHODS: Coding regions of the deafness genes were captured by a hybridization-based method and processed through the standard next-generation sequencing (NGS) protocol using the Illumina platform. Samples hybridized together in the same reaction were analyzed to obtain CNVs. A read depth based method was used to measure CNVs at the resolution of a single exon. Results were validated by the quantitative PCR (qPCR) based method. RESULTS: Among 79 sporadic cases clinically diagnosed with sensorineural hearing loss, we identified previously-reported disease-causing sequence mutations in 16 cases. In addition, we identified a total of 97 CNVs (72 CNV gains and 25 CNV losses) in 27 deafness genes. The CNVs included homozygous deletions which may directly give rise to deleterious effects on protein functions known to be essential for hearing, as well as heterozygous deletions and CNV gains compounded with sequence mutations in deafness genes that could potentially harm gene functions. CONCLUSIONS: We studied how CNVs in known deafness genes may result in deafness. Data provided here served as a basis to explain how CNVs disrupt normal functions of deafness genes. These results may significantly expand our understanding about how various types of genetic mutations cause deafness in humans.