Journal of Human Genetics最新文献_第4页

Assessment of ability of a DNA language model to predict pathogenicity of rare coding variants. DNA语言模型预测罕见编码变异致病性的能力评估。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-15 DOI: 10.1038/s10038-025-01385-3

David Curtis

引用次数: 0

Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis. 中国多发性骨软骨瘤和强直性脊柱炎家族中IL17RC错义变异的鉴定

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-14 DOI: 10.1038/s10038-025-01383-5

Yingchun Zheng, Xuewu Wei, Zhongzhi Gan, Mingming Zhang, Zongrui Shen, Shunfei Ma, Yihao Huang, Fei He, Jian Wang, Fu Xiong

{"title":"Identification of an IL17RC missense variant in a Chinese family with multiple osteochondromas and ankylosing spondylitis.","authors":"Yingchun Zheng, Xuewu Wei, Zhongzhi Gan, Mingming Zhang, Zongrui Shen, Shunfei Ma, Yihao Huang, Fei He, Jian Wang, Fu Xiong","doi":"10.1038/s10038-025-01383-5","DOIUrl":"https://doi.org/10.1038/s10038-025-01383-5","url":null,"abstract":"Ankylosing spondylitis (AS) is a chronic and progressive inflammatory arthritis involving disorders of both the immune and skeletal systems. Multiple osteochondromas (MO) is a rare skeletal disorder with a variety of clinical manifestations characterized by multiple benign exostoses. Here, we investigate a Chinese family with HLA-B27-negative AS complicated with MO. Whole-exome sequencing (WES) and Sanger sequencing were used to screen and identify the pathogenic gene. In vitro functional analysis was performed, and a pathogenesis-associated interleukin (IL)-17 receptor C (IL17RC) mutation was analyzed to investigate its effect on phenotypes. WES was used to identify a known missense mutation, NM_000127.3:c.1019 G > A(p.Arg340His), in the pathogenic gene EXT1 that is causal for MO. Moreover, a missense mutation, NM_153461.3:c.1067 C > T(p.Thr356Met), in the IL17RC gene was identified as potentially responsible for AS or spondyloarthritis symptoms in this family. In vitro over-expression of mutant IL17RC decreased its expression and increased the expression of IL17RA, consistent with the expression of these two genes in patients. Mechanistically, mutant IL17RC enhanced the activation of the NF-κB pathway. This study increases our understanding of the pathogenesis and progression of these diseases. Our findings broaden the risk factors in non-HLA-B genes associated with the NF-κB pathway in AS.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analyzing complex traits and diseases using GxE PRS: genotype-environment interaction in polygenic risk score models. 利用GxE - PRS分析复杂性状和疾病：多基因风险评分模型中的基因型-环境相互作用。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-14 DOI: 10.1038/s10038-025-01378-2

Dovini Jayasinghe, Vu Viet Hoang Pham, Kerri Beckmann, Beben Benyamin, S Hong Lee

{"title":"Analyzing complex traits and diseases using GxE PRS: genotype-environment interaction in polygenic risk score models.","authors":"Dovini Jayasinghe, Vu Viet Hoang Pham, Kerri Beckmann, Beben Benyamin, S Hong Lee","doi":"10.1038/s10038-025-01378-2","DOIUrl":"10.1038/s10038-025-01378-2","url":null,"abstract":"A deeper understanding of how environmental factors influence genetic risks is crucial for exploring their combined effects on health outcomes. This can be effectively achieved by incorporating genotype-environment (GxE) interactions in polygenic risk score (PRS) models. We applied our recently developed GxEprs model to a wide range of obesity-related complex traits and diseases, leveraging data from the UK Biobank, to capture significant GxE signals. This work represents the first application of the \"GxEprs\" method, designed to minimize issues with spurious GxE signals and model misspecification. We identified significant GxE signals especially in quantitative phenotypes such as body mass index (BMI), waist-to-hip ratio (WHR), body fat percentage (BF) and waist circumference (WC) and our results indicated a significant enhancement in prediction accuracy in most traits, highlighting the importance of the GxE component. This study demonstrated the potential of incorporating GxE interactions in PRS models, offering a broad understanding of genetic risks and laying foundation in applying these insights in personalized medicine.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Why are men taller than women?: Genetic and hormonal factors involved in sex differences in human height. 为什么男人比女人高？基因和荷尔蒙因素与人类身高的性别差异有关。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-14 DOI: 10.1038/s10038-025-01384-4

Maki Fukami, Tsutomu Ogata, Atsushi Hattori

引用次数: 0

Genetic insights into the origin, admixture, and migration of the early Austronesian peoples. 对早期南岛人的起源、混合和迁移的遗传学见解。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-07 DOI: 10.1038/s10038-025-01380-8

Albert Min-Shan Ko, Hung-Pin Tu, Ying-Chin Ko

{"title":"Genetic insights into the origin, admixture, and migration of the early Austronesian peoples.","authors":"Albert Min-Shan Ko, Hung-Pin Tu, Ying-Chin Ko","doi":"10.1038/s10038-025-01380-8","DOIUrl":"https://doi.org/10.1038/s10038-025-01380-8","url":null,"abstract":"It is understood that Austronesian ancestors appeared in Taiwan ~6 thousand years ago (Kya), and later expanded beyond Taiwan, but their early origins and relationships with people outside Taiwan remain uncertain. By reconstructing phylogenetic patterns and phylogeographical distribution from mitochondrial and Y haplogroups and genome-wide data, new evidence shows that the Pre-Austronesians may have originated in the coastal southeastern China (centered on Fujian) during the very early Neolithic Age (>10Kya) and lived on the marine subsistence in addition to hunting-gathering. They subsequently mixed with some ancient northern Chinese (from Shandong) and introduced mixed millets and rice cultivation, forming the Proto-Austronesian people ~7-10Kya. Later, Early Austronesians (~4-7Kya) evolved and migrated to Taiwan (~6Kya), and then spread to Island Southeast Asia (ISEA), Champa, southern Thailand, Madagascar, and Oceania via the Philippines (~4.1Kya). The second source is the Austroasiatic ancestors, who originated in southern China in the early Neolithic Age and migrated to the ISEA via the Mainland Southeast Asia and Malay Peninsula in the late Neolithic Age. They mixed with the core Austronesian speakers from Taiwan to become Austronesian speakers, and spread to Oceania. Linguistic and archaeological findings also support the Austronesian origins and genetic prehistory. Most recently, some Austronesians of ISEA have mixed with newcomers from South Asia. The Austronesian ancestors neither originated in the ISEA nor migrated directly from mainland China to the Philippines, also has nothing to do with the so-called \"two-layer\" hypothesis. Future research requires more Paleolithic and Neolithic genetic evidence, improved genetic age estimates, and multidisciplinary consistency.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144799354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel m.14677 T > C variant in mitochondrial tRNAGlu gene causes chronic progressive external ophthalmoplegia 小说m.14677线粒体tRNAGlu基因突变引起慢性进行性外眼肌麻痹。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-06 DOI: 10.1038/s10038-025-01381-7

Nahoko Katayama Ueda, Masakazu Mimaki, Shota Ito, Ayuka Murakami, Satoshi Yokoi, Ichizo Nishino, Masahisa Katsuno, Yu-ichi Goto

{"title":"A novel m.14677 T > C variant in mitochondrial tRNAGlu gene causes chronic progressive external ophthalmoplegia","authors":"Nahoko Katayama Ueda, Masakazu Mimaki, Shota Ito, Ayuka Murakami, Satoshi Yokoi, Ichizo Nishino, Masahisa Katsuno, Yu-ichi Goto","doi":"10.1038/s10038-025-01381-7","DOIUrl":"10.1038/s10038-025-01381-7","url":null,"abstract":"Chronic progressive external ophthalmoplegia (CPEO) is a mitochondrial disease characterized by progressive ptosis and ophthalmoplegia, caused by single deletions, point mutations, or multiple deletions in mitochondrial DNA (mtDNA). Most point mutations occur in tRNA genes. Here, we report a novel variant of the tRNAGlu gene associated with CPEO. A 45-year-old male presented with ptosis and external ophthalmoplegia; however, blood test results, including lactate levels and autoantibodies, were normal. CPEO was suspended, prompting additional myopathological examination, mtDNA sequencing analysis, long polymerase chain reaction (PCR) analysis, and single-fiber analysis to compare mutation loads between ragged-red fibers (RRFs) and non-RRFs. Histopathological examination revealed scattered COX-negative RRFs. No deletions were found in the mtDNA. MtDNA sequencing analysis revealed a novel variant, m.14677 T > C, in the tRNAGlu gene, with Sanger sequencing indicating 45% heteroplasmy in the muscle tissue. Single-fiber analysis showed a significantly higher mutation load of m.14677 T > C in RRFs (range: 25.3–92.8%; median: 88.1%; n = 6) compared with non-RRFs (range: 3.5–85.9%; median: 17.1%; n = 5) (P = 0.03). Based on the significantly higher mutation load in RRFs than in non-RRFs, pathological evidence of mitochondrial disease, and the mutation’s occurrence at an evolutionarily conserved site, we concluded that m.14677 T > C, a novel variant of the tRNAGlu gene, is the cause of CPEO. Biochemical and histopathological examinations of muscle tissue, combined with single-fiber analysis, are valuable tools for evaluating mtDNA variants, particularly those within tRNA genes.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":"70 10","pages":"537-540"},"PeriodicalIF":2.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s10038-025-01381-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular genetics of skeletal muscle channelopathies. 骨骼肌通道病的分子遗传学。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-06 DOI: 10.1038/s10038-025-01370-w

Tomoya Kubota, Masanori P Takahashi

引用次数: 0

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-08-06 DOI: 10.1038/s10038-025-01377-3

Hisatoshi Hanamatsu, Goki Suda, Masatsugu Ohara, Masaki Kurogochi, Naoya Sakamoto, Jun-Ichi Furukawa

{"title":"Novel glycan-related biomarker discovery by total glycomic and focused protein glycomic analyses.","authors":"Hisatoshi Hanamatsu, Goki Suda, Masatsugu Ohara, Masaki Kurogochi, Naoya Sakamoto, Jun-Ichi Furukawa","doi":"10.1038/s10038-025-01377-3","DOIUrl":"https://doi.org/10.1038/s10038-025-01377-3","url":null,"abstract":"The cell surface is covered with a variety of glycan subtypes (sub-glycans) such as N-glycans, O-glycans, glycosphingolipid-glycans, and glycosaminoglycans, which are collectively called the glycocalyx. The expression patterns of sub-glycans change in response to various biological events during disease pathogenesis; however, the structures of all major sub-glycans and their relative concentrations in a cell have been hardly reported. Total glycomic analysis, which comprehensively measures all major sub-glycans, is a powerful tool to discover cellular and clinical biomarkers. In this review, we provide an overview of the analytical methods for sub-glycans and the total glycome in cultured cell lines, human serum, mouse brain tissue, and human osteoarthritis cartilage. This approach not only facilitates characterization of cells, but also has applications for hierarchical clustering analysis, glycan-related biomarker discovery, and investigation of the relationship between sub-glycans and gene expression levels using the total glycome. Moreover, we discuss our recent research focused on identifying potential biomarkers of nonalcoholic fatty liver disease. These glycomic technologies are expected to contribute to diagnostics and drug development for rare diseases in the future.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144794621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

When ganglioside pathways go awry: congenital disorders and experimental insights. 当神经节苷脂通路出错：先天性疾病和实验见解。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-31 DOI: 10.1038/s10038-025-01366-6

Kei-Ichiro Inamori, Jin-Ichi Inokuchi

{"title":"When ganglioside pathways go awry: congenital disorders and experimental insights.","authors":"Kei-Ichiro Inamori, Jin-Ichi Inokuchi","doi":"10.1038/s10038-025-01366-6","DOIUrl":"https://doi.org/10.1038/s10038-025-01366-6","url":null,"abstract":"Glycosphingolipids comprise a hydrophobic ceramide backbone, consisting of a long-chain base (sphingosine) and a fatty acid, conjugated with a hydrophilic oligosaccharide moiety. These amphipathic molecules are integral constituents of cellular membranes, playing pivotal roles in modulating membrane protein functionality and receptor-mediated signaling. Among glycosphingolipids, gangliosides, defined by their inclusion of sialic acid residues, are abundantly enriched in the central nervous system. Notably, four predominant species, GM1, GD1a, GD1b, and GT1b, constitute the majority of gangliosides in the mammalian brain and are indispensable for neuronal development, synaptic architecture, and signal transduction. These gangliosides are critically involved in neurogenesis, differentiation, membrane stability, and the modulation of receptor function, ion channel activity, and immunological signaling within the nervous system. The biosynthesis of these gangliosides is orchestrated by key enzymes, including GM3 synthase (ST3GAL5) and GM2/GD2 synthase (B4GALNT1) catalyzing the formation of downstream intermediates. Pathogenic variants in ST3GAL5 result in GM3 synthase deficiency (GM3SD), an autosomal recessive disorder characterized by infantile-onset epileptic encephalopathy and profound developmental regression. In contrast, biallelic mutations in B4GALNT1 cause a complex form of hereditary spastic paraplegia (SPG26), marked by progressive spasticity and intellectual impairment. ST3GAL3, another α2,3-sialyltransferase, contributes to the synthesis of GD1a and GT1b, as well as to glycoprotein sialylation. Mutations in this gene underlie neurodevelopmental disorders, including developmental and epileptic encephalopathy type 15 (DEE15). In this review, we summarize the current understanding of the molecular pathogenesis of congenital ganglioside biosynthesis disorders, integrating data from genetically engineered mouse models and affected individuals.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144760308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetics of myositis - distinct backgrounds of subtypes. 肌炎的遗传学-不同亚型的背景。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2025-07-30 DOI: 10.1038/s10038-025-01374-6

Akinori Uruha

引用次数: 0