Journal of Genetics and Genomics最新文献

GJB2-related hearing loss is the most common type of hereditary deafness worldwide. However, its complex inheritance patterns, diverse phenotypic manifestations, and population-specific variant spectrum present significant challenges for both clinical practice and research. This review synthesizes evidence from 215 studies (7967 patients) to quantitatively analyze the natural history and genotype-phenotype correlations across different inheritance patterns, including recessive, dominant, and digenic forms. Among V37I, the V37I/NT genotype is associated with a high proportion of mild-to-moderate hearing loss (84.15%), and the V37I/T genotype shows a flatter configuration than V37I/V37I. An analysis of 178 syndromic cases reveals complex phenotypes involving both the skin and auditory system, characterized by early-onset and severe hearing loss, with clear genotype-phenotype correlations for specific variants. We also summarize genomic and epigenetic mechanisms contributing to phenotypic severity. With a focus on clinical translation, we review the trajectory of GJB2 gene therapy research, from foundational animal studies to innovative therapeutic strategies approaching clinical application. By evaluating the natural history and genotype-specific auditory profiles, this work provides a practical evidence base to guide prognosis, genetic counseling, and crucially, the design of upcoming clinical trials, including patient selection and efficacy assessment. This review is registered with PROSPERO (CRD420251243620).

Photorespiration is an essential metabolic process in C₃ plants, yet it imposes a significant carbon losses of up to 30% or more. Synthetic biology has recently enabled the engineering of diverse photorespiratory bypasses to overcome this limitation. In this review, we categorize these bypasses into three major types based on glycolate carbon retention and CO₂ release. The first are chloroplast-localized carbon-releasing bypasses, which shift CO₂ release from mitochondria to chloroplasts, thereby establishing a localized CO₂-concentrating mechanism around Rubisco. The second are carbon-neutral bypasses, which conserve carbon during glycolate metabolism, thereby avoiding net carbon loss and often coupling bypasses with nitrogen assimilation. The third are carbon-positive bypasses, which not only minimize carbon loss but also achieve net carbon gain. We also emphasize some bypasses that redirect glycolate flow toward the production of more valuable metabolites, such as amino acids and organic acids. These strategies reveal that by reprogramming glycolate metabolism, it is possible to overcome the inherent photorespiratory limitations and increase photosynthetic efficiency in C₃ crops. Overall, this review offers an overview of current genetic strategies for suppressing photorespiration in model plants and crops and guides future optimization and rational design of photorespiratory bypasses.

As a fundamental feature of plant cells, the cell wall sculpts plant architecture and governs environmental interactions. The cell wall is a dynamic matrix that exhibits both rigidity and plasticity, not only providing structural support but also serving as a critical signaling hub to regulate plant growth, development, and stress adaptation. Although long underappreciated, the signaling role of the cell wall has been brought to the forefront by recent breakthroughs, which have profoundly advanced our understanding of its importance and regulatory mechanisms. In this review, we summarize recent progress in cell wall signaling, particularly focusing on cell wall-derived signals, cell wall sensing mechanisms, and the functional roles of cell wall signaling in plant vegetative growth, reproduction, and abiotic stress responses.

Leber hereditary optic neuropathy (LHON) is a paradigm for mitochondrial retinopathy. Here, we investigate the mechanism underlying the interaction between nuclear modifier and mtDNA mutation(s) that manifests optic neuropathy in vivo to develop an effective therapeutic approach for this disease using mouse models bearing LHON-linked Yars2^G186V or COI^V421A mutation alone and double mutations. Yars2^G186V alters mitochondrial translation and assembly and activities of complex I, III, and IV, while COI^V421A reduces complex IV activity. However, a single Yars2^G186V or COI^V421A mutation causes mild declines in ATP production and yields relatively mild degeneration of retinal ganglion cells (RGCs). Notably, the synergy between COI^V421A and Yars2^G186V mutations aggravates mitochondrial dysfunction and oxidative stress. Interestingly, COI^V421A mainly promotes apoptosis, and Yars2^G186V contributes to ferroptosis. The combination of two mutations accelerates the degeneration of RGCs and photoreceptors. Strikingly, AAV-mediated Yars2 expression in the mouse retina carrying both Yars2^G186V and COI^V421A mutations corrects the defective translation and ferroptosis arising from the Yars2^G186V mutation and remarkably improves mitochondrial function and causes morphologic and functional recovery of RGCs and photoreceptors. These findings provide mechanistic insights into the pathophysiology of LHON arising from nuclear modifiers and mtDNA mutation(s) and potential therapeutic strategies for LHON and other mitochondrial diseases.

The Taizhou Longitudinal Study (TZL) is a population-based prospective cohort initiated in 2007, recruiting over 201,000 adults aged 20-80 from urban and rural areas of Taizhou, Jiangsu Province, China. The cohort is extensively phenotyped through baseline questionnaire-based interviews, physical examinations, biochemical assays, and longitudinal follow-up using health records and repeated assessments. A wide range of biospecimens, including blood, urine, saliva, and feces, have been collected to enable omics-level profiling. Genome-wide genotyping has been performed for approximately 50,000 participants recruited from 2009 to 2014. Here, we present an integrated overview of the existing and planned genetic and phenotypic resources, describe genotyping and quality control procedures, and assess cryptic relatedness and population structure, followed by genome-wide association analyses of 66 physical and biochemical traits. In total, 533 independent loci reach Bonferroni significance after clumping. These analyses identify 55 previously unreported loci, demonstrating the capacity of the TZL to elucidate the genetic architecture of complex traits in East Asian populations. By integrating high-quality phenotypic and genotypic data, the TZL enables a comprehensive investigation of gene-environment interactions in Chinese population. With ongoing expansions and development of a controlled-access data-sharing platform, the TZL is positioned as a valuable resource for precision medicine and public health research.

The thalamus regulates sensory processing, cognition, and sleep, yet the molecular mechanisms underlying its development remain incompletely understood. Long noncoding RNAs (lncRNAs), particularly evolutionarily conserved ones, are highly enriched in the brain. Using public mRNA databases, we screen for lncRNAs with embryonic brain expression and harboring ultraconserved non-coding elements (UCNEs) in humans and mice, identifying colorectal neoplasia differentially expressed (Crnde). It exhibits stage-specific upregulation in the embryonic thalamus. The Database of Genomic Variation and Phenotype in Humans using Ensembl Resources (DECIPHER) database suggests a potential association between Crnde and intellectual disability. Crnde-deficient mice display anxiety-like behaviors and spatial memory deficits. Furthermore, Crnde ablation increases progenitor cell numbers and impairs neuronal differentiation during embryonic thalamic development. Mechanistically, Crnde modulates the mRNA expression of gastrulation brain homeobox 2 (Gbx2), a gene critical for thalamic development. Collectively, our results implicate lncRNA Crnde in the proper progression of embryonic thalamic development in mice.

Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and ultimately, respiratory failure. Despite a growing understanding of its complex pathophysiology, therapeutic options remain limited. This review critically analyzes recent clinical advances by comparing two divergent strategies, including precision gene-targeted therapies for monogenic ALS subtypes and broad-spectrum agents for the wider sporadic population. While gene therapies like tofersen demonstrate clear molecular target engagement, their translation to robust clinical benefit remains a challenge. In contrast, broad-spectrum agents have faced consistent late-stage failures, often due to the disease's underlying diversity, which undermines a one-size-fits-all approach. We argue that this heterogeneity, coupled with a lack of predictive biomarkers and the difficulty of late-stage intervention, represents the core barrier to progress. The future of ALS therapeutics therefore depends on a strategic pivot toward personalized medicine. This requires prospectively stratifying patients, developing rational combination therapies, and intervening earlier in the disease course, ultimately treating ALS as a syndrome of distinct molecular diseases rather than a single entity.