American journal of human genetics最新文献

{"title":"Demographic history and genetic variation of the Armenian population.","authors":"Anahit Hovhannisyan, Pierpaolo Maisano Delser, Anna Hakobyan, Eppie R Jones, Joshua G Schraiber, Mariya Antonosyan, Ashot Margaryan, Zhe Xue, Sungwon Jeon, Jong Bhak, Peter Hrechdakian, Hovhannes Sahakyan, Lehti Saag, Zaruhi Khachatryan, Levon Yepiskoposyan, Andrea Manica","doi":"10.1016/j.ajhg.2024.10.022","DOIUrl":"10.1016/j.ajhg.2024.10.022","url":null,"abstract":"<p><p>We introduce a sizable (n = 34) whole-genome dataset on Armenians, a population inhabiting the region in West Asia known as the Armenian highlands. Equipped with this genetic data, we conducted a whole-genome study of Armenians and deciphered their fine-scale population structure and complex demographic history. We demonstrated that the Armenian populations from western, central, and eastern parts of the highlands are relatively homogeneous. The Sasun, a population in the south that had been argued to have received a major genetic contribution from Assyrians, was instead shown to have derived its slightly divergent genetic profile from a bottleneck that occurred in the recent past. We also investigated the debated question on the genetic origin of Armenians and failed to find any significant support for historical suggestions by Herodotus of their Balkan-related ancestry. We checked the degree of continuity of modern Armenians with ancient inhabitants of the eastern Armenian highlands and detected a genetic input into the region from a source linked to Neolithic Levantine Farmers at some point after the Early Bronze Age. Additionally, we cataloged an abundance of new mutations unique to the population, including a missense mutation predicted to cause familial Mediterranean fever, an autoinflammatory disorder highly prevalent in Armenians. Thus, we highlight the importance of further genetic and medical studies of this population.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"11-27"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome X-wide common variant association study in autism spectrum disorder.","authors":"Marla Mendes, Desmond Zeya Chen, Worrawat Engchuan, Thiago Peixoto Leal, Bhooma Thiruvahindrapuram, Brett Trost, Jennifer L Howe, Giovanna Pellecchia, Thomas Nalpathamkalam, Roumiana Alexandrova, Nelson Bautista Salazar, Ethan A McKee, Natalia Rivera-Alfaro, Meng-Chuan Lai, Sara Bandres-Ciga, Delnaz Roshandel, Clarrisa A Bradley, Evdokia Anagnostou, Lei Sun, Stephen W Scherer","doi":"10.1016/j.ajhg.2024.11.008","DOIUrl":"10.1016/j.ajhg.2024.11.008","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2, DDX3X, and DMD. The \"female protective effect\" in ASD suggests that females may require a higher genetic burden to manifest symptoms similar to those in males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leaves them underrepresented in genome-wide studies. Here, we conducted an X-chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Collection (SSC), and Simons Powering Autism Research (SPARK), alongside 8,981 population controls (43% males). We analyzed 418,652 X chromosome variants, identifying 59 associated with ASD (p values 7.9 × 10^-6 to 1.51 × 10^-5), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on Xp22.2 (lead SNP rs12687599, p = 3.57 × 10^-7) harboring ASB9/ASB11 and another encompassing DDX53 and the PTCHD1-AS long non-coding RNA (lead SNP rs5926125, p = 9.47 × 10^-6). When mapping genes within 10 kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD (GRPR, AP1S2, DDX53, HDAC8, PCDH19, PTCHD1, PCDH11X, PTCHD1-AS, DMD, SYAP1, CNKSR2, GLRA2, OFD1, CDKL5, GPRASP2, NXF5, and SH3KBP1). FGF13 emerged as an X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"135-153"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pan-cancer analysis reveals age-associated genetic alterations in protein domains.","authors":"Haozhe Zou, Si Li, Jiyu Guo, Luan Wen, Chongwen Lv, Feng Leng, Zefeng Chen, Mengqian Zeng, Juan Xu, Yongsheng Li, Xia Li","doi":"10.1016/j.ajhg.2024.11.011","DOIUrl":"10.1016/j.ajhg.2024.11.011","url":null,"abstract":"<p><p>Cancer incidence and mortality differ among individuals of different ages, but the functional consequences of genetic alterations remain largely unknown. We systematically characterized genetic alterations within protein domains stratified by affected individual's age and showed that the mutational effects on domains varied with age. We further identified potential age-associated driver genes with hotspots across 33 cancers. The candidate drivers involved numerous cancer-related genes that participate in various oncogenic pathways and play central roles in human protein-protein interaction (PPI) networks. We found widespread age biases in protein domains and identified the associations between hotspots and age. Age-stratified PPI networks perturbed by hotspots were constructed to illustrate the function of mutations enriched in domains. We found that hotspots in young adults were associated with premature senescence. In summary, we provided a catalog of age-associated hotspots and their perturbed networks, which may facilitate precision diagnostics and treatments for cancer.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"44-58"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts.","authors":"Hannah M Smith, Hong Kiat Ng, Joanna E Moodie, Danni A Gadd, Daniel L McCartney, Elena Bernabeu, Archie Campbell, Paul Redmond, Adele Taylor, Danielle Page, Janie Corley, Sarah E Harris, Darwin Tay, Ian J Deary, Kathryn L Evans, Matthew R Robinson, John C Chambers, Marie Loh, Simon R Cox, Riccardo E Marioni, Robert F Hillary","doi":"10.1016/j.ajhg.2024.11.012","DOIUrl":"10.1016/j.ajhg.2024.11.012","url":null,"abstract":"<p><p>Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort. We observed a maximum of 12,033 significant findings (p < 3.6 × 10^-8) for BMI in a marginal linear regression EWAS. By contrast, a joint and conditional Bayesian penalized regression approach yielded 27 high-confidence associations with BMI. EpiScores trained in GS performed well in both Scottish and Singaporean test cohorts (Lothian Birth Cohort 1936 [LBC1936] and Health for Life in Singapore [HELIOS]). The EpiScores for BMI and total cholesterol performed best in HELIOS, explaining 20.8% and 7.1% of the variance in the measured traits, respectively. The corresponding results in LBC1936 were 14.4% and 3.2%, respectively. Differences were observed in HELIOS for body fat, where the EpiScore explained ∼9% of the variance in Chinese and Malay -subgroups but ∼3% in the Indian subgroup. The EpiScores also correlated with cognitive function in LBC1936 (standardized β_range: 0.08-0.12, false discovery rate p [p_FDR] < 0.05). Accounting for the correlation structure across the methylome can vastly affect the number of lead findings in EWASs. The EpiScores of metabolic traits are broadly applicable across populations and can reflect differences in cognition.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"106-115"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When \"loss-of-function\" means proteostasis burden: Thinking again about coding DNA variants.","authors":"Claire L Shovlin, Micheala A Aldred","doi":"10.1016/j.ajhg.2024.12.002","DOIUrl":"10.1016/j.ajhg.2024.12.002","url":null,"abstract":"<p><p>Each human genome has approximately 5 million DNA variants. Even for complete loss-of-function variants causing inherited, monogenic diseases, current understanding based on gene-specific molecular function does not adequately predict variability observed between people with identical mutations or fluctuating disease trajectories. We present a parallel paradigm for loss-of-function variants based on broader consequences to the cell when aberrant polypeptide chains of amino acids are translated from mutant RNA to generate mutated proteins. Missense variants that modify primary amino acid sequence, and nonsense/frameshift variants that generate premature termination codons (PTCs), are placed in context alongside emergent themes of chaperone binding, protein quality control capacity, and cellular adaptation to stress. Relatively stable proteostasis burdens are contrasted with rapid changes after induction of gene expression, or stress responses that suppress nonsense mediated decay (NMD) leading to higher PTC transcript levels where mutant proteins can augment cellular stress. For known disease-causal mutations, an adjunctive variant categorization system enhances clinical predictive power and precision therapeutic opportunities. Additionally, with typically more than 100 nonsense and frameshift variants, and ∼10,000 missense variants per human DNA, the paradigm focuses attention on all protein-coding DNA variants, and their potential contributions to multimorbid states beyond classically designated inherited diseases. Experimental testing in clinically relevant systems is encouraged to augment current atlases of protein expression at single-cell resolution, and high-throughput experimental data and deep-learning models that predict which amino acid substitutions generate enhanced degradative burdens. Incorporating additional dimensions such as pan-proteome competition for chaperones, and age-related loss of proteostasis capacity, should further accelerate health impacts.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"3-10"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic functional characterization of non-coding regulatory SNPs associated with central obesity.","authors":"Shan-Shan Dong, Yuan-Yuan Duan, Ren-Jie Zhu, Ying-Ying Jia, Jia-Xin Chen, Xiao-Ting Huang, Shi-Hao Tang, Ke Yu, Wei Shi, Xiao-Feng Chen, Feng Jiang, Ruo-Han Hao, Yunlong Liu, Zhongbo Liu, Yan Guo, Tie-Lin Yang","doi":"10.1016/j.ajhg.2024.11.005","DOIUrl":"10.1016/j.ajhg.2024.11.005","url":null,"abstract":"<p><p>Central obesity is associated with higher risk of developing a wide range of diseases independent of overall obesity. Genome-wide association studies (GWASs) have identified more than 300 susceptibility loci associated with central obesity. However, the functional understanding of these loci is limited by the fact that most loci are in non-coding regions. To address this issue, our study first prioritized 2,034 single-nucleotide polymorphisms (SNPs) based on fine-mapping and epigenomic annotation analysis. Subsequently, we employed self-transcribing active regulatory region sequencing (STARR-seq) to systematically evaluate the enhancer activity of these prioritized SNPs. The resulting data analysis identified 141 SNPs with allelic enhancer activity. Further analysis of allelic transcription factor (TF) binding prioritized 20 key TFs mediating the central-obesity-relevant genetic regulatory network. Finally, as an example, we illustrate the molecular mechanisms of how rs8079062 acts as an allele-specific enhancer to regulate the expression of its targeted RNF157. We also evaluated the role of RNF157 in the adipogenic differentiation process. In conclusion, our results provide an important resource for understanding the genetic regulatory mechanisms underlying central obesity.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"116-134"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mendelian genetics and eugenics.","authors":"Walter F Bodmer, Brian Charlesworth","doi":"10.1016/j.ajhg.2024.12.003","DOIUrl":"10.1016/j.ajhg.2024.12.003","url":null,"abstract":"","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"196-197"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in EP400, encoding a chromatin remodeler, cause epilepsy with neurodevelopmental disorders.","authors":"Sheng Luo, Peng-Yu Wang, Peng Zhou, Wen-Jun Zhang, Yu-Jie Gu, Xiao-Yu Liang, Jing-Wen Zhang, Jun-Xia Luo, Hong-Wei Zhang, Song Lan, Ting-Ting Zhang, Jie-Hua Yang, Su-Zhen Sun, Xiang-Yang Guo, Ju-Li Wang, Lin-Fan Deng, Ze-Hai Xu, Liang Jin, Yun-Yan He, Zi-Long Ye, Wei-Yue Gu, Bing-Mei Li, Yi-Wu Shi, Xiao-Rong Liu, Hong-Jun Yan, Yong-Hong Yi, Yu-Wu Jiang, Xiao Mao, Wen-Ling Li, Heng Meng, Wei-Ping Liao","doi":"10.1016/j.ajhg.2024.11.010","DOIUrl":"10.1016/j.ajhg.2024.11.010","url":null,"abstract":"<p><p>EP400 encodes a core catalytic ATPase subunit of ATP-dependent chromatin remodeling complexes. The gene-disease association of EP400 is undetermined. In this study, we performed trio-based whole-exome sequencing in a cohort of 402 families with epilepsy and neurodevelopmental disorders (NDDs) and identified compound heterozygous EP400 variants in six unrelated individuals. Six additional EP400 individuals were recruited via the match platform of China, including two de novo heterozygous and four compound heterozygous variants. The individual with a heterozygous de novo frameshift variant presented with NDDs, while the others exhibited epilepsy and NDDs, explained by the damaged genetic dependence quantity. EP400 presented significantly higher excesses of variants in the individuals. Clustering analysis revealed that the majority paralogs of EP400 were associated with NDDs/epilepsy and co-expressed highly with EP400. Analysis of the spatiotemporal expression indicated that EP400 is highly expressed in the developing brain and cells during differentiation, indicating its vital role in neurodevelopment; EP400 is predominantly expressed in inhibitory neurons in the early stage but in excitatory neurons in the mature stage. The development-dependent expression pattern of neuron specificity explained the favorable outcome of epilepsy. Knockdown of EP400 ortholog in Drosophila caused significantly increased susceptibility to seizures and abnormal neuronal firing. The ep400 crispant zebrafish exhibited brain developmental abnormalities, poorer adaptability, lower response to stimulation, epileptic discharges, abnormal cellular apoptosis, and increased susceptibility to seizures. Transcriptome analysis showed that ep400 deficiency caused expressional dysregulation of 84 epilepsy/NDD-associated genes, including 11 highly dose-sensitive genes. This study identified EP400 as a causative gene of epilepsy/NDDs.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":" ","pages":"87-105"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EEFSEC deficiency: A selenopathy with early-onset neurodegeneration.","authors":"Lucia Laugwitz, Rebecca Buchert, Patricio Olguín, Mehrdad A Estiar, Mihaela Atanasova, Wilson Marques Jr, Jörg Enssle, Brian Marsden, Javiera Avilés, Andrés González-Gutiérrez, Noemi Candia, Marietta Fabiano, Susanne Morlot, Susana Peralta, Alisa Groh, Carmen Schillinger, Carolin Kuehn, Linda Sofan, Marc Sturm, Benjamin Bender, Pedro J Tomaselli, Uta Diebold, Amelie J Mueller, Stephanie Spranger, Maren Fuchs, Fernando Freua, Uirá Souto Melo, Lauren Mattas, Setareh Ashtiani, Oksana Suchowersky, Samuel Groeschel, Guy A Rouleau, Keren Yosovich, Marina Michelson, Zvi Leibovitz, Muhammad Bilal, Eyyup Uctepe, Ahmet Yesilyurt, Orhan Ozdogan, Tamer Celik, Ingeborg Krägeloh-Mann, Olaf Riess, Hendrik Rosewich, Muhammad Umair, Dorit Lev, Stephan Zuchner, Ulrich Schweizer, David S Lynch, Ziv Gan-Or, Tobias B Haack","doi":"10.1016/j.ajhg.2024.12.001","DOIUrl":"10.1016/j.ajhg.2024.12.001","url":null,"abstract":"<p><p>Inborn errors of selenoprotein expression arise from deleterious variants in genes encoding selenoproteins or selenoprotein biosynthetic factors, some of which are associated with neurodegenerative disorders. This study shows that bi-allelic selenocysteine tRNA-specific eukaryotic elongation factor (EEFSEC) variants cause selenoprotein deficiency, leading to progressive neurodegeneration. EEFSEC deficiency, an autosomal recessive disorder, manifests with global developmental delay, progressive spasticity, ataxia, and seizures. Cerebral MRI primarily demonstrated a cerebellar pathology, including hypoplasia and progressive atrophy. Exome or genome sequencing identified six different bi-allelic EEFSEC variants in nine individuals from eight unrelated families. These variants showed reduced EEFSEC function in vitro, leading to lower levels of selenoproteins in fibroblasts. In line with the clinical phenotype, an eEFSec-RNAi Drosophila model displays progressive impairment of motor function, which is reflected in the synaptic defects in this model organisms. This study identifies EEFSEC deficiency as an inborn error of selenocysteine metabolism. It reveals the pathophysiological mechanisms of neurodegeneration linked to selenoprotein metabolism, suggesting potential targeted therapies.</p>","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"112 1","pages":"168-180"},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous UBR5 variants result in a neurodevelopmental syndrome with developmental delay, autism, and intellectual disability.","authors":"Pascale Sabeh,Samantha A Dumas,Claudia Maios,Hiba Daghar,Marek Korzeniowski,Justine Rousseau,Matthew Lines,Andrea Guerin,John J Millichap,Megan Landsverk,Theresa Grebe,Kristin Lindstrom,Jonathan Strober,Tarik Ait Mouhoub,Christiane Zweier,Michelle Steinraths,Moritz Hebebrand,Bert Callewaert,Rami Abou Jamra,Monika Kautza-Lucht,Meret Wegler,Paul Kruszka,Candy Kumps,Ehud Banne,Marta Biderman Waberski,Anne Dieux,Sarah Raible,Ian Krantz,Livija Medne,Kieran Pechter,Laurent Villard,Renzo Guerrini,Claudia Bianchini,Carmen Barba,Davide Mei,Xavier Blanc,Christine Kallay,Emmanuelle Ranza,Xiao-Ru Yang,Emily O'Heir,Kirsten A Donald,Serini Murugasen,Zandre Bruwer,Muge Calikoglu,Jennifer M Mathews,Marion Lesieur-Sebellin,Geneviève Baujat,Nicolas Derive,Tyler Mark Pierson,Jill R Murrell,Amelle Shillington,Clothilde Ormieres,Sophie Rondeau,André Reis,Alberto Fernandez-Jaen,Ping Yee Billie Au,David A Sweetser,Lauren C Briere,Nathalie Couque,Laurence Perrin,Jennifer Schymick,Paul Gueguen,Mathilde Lefebvre,Michael Van Andel,Jane Juusola,Stylianos E Antonarakis,J Alex Parker,Barrington G Burnett,Philippe M Campeau","doi":"10.1016/j.ajhg.2024.11.009","DOIUrl":"https://doi.org/10.1016/j.ajhg.2024.11.009","url":null,"abstract":"E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.","PeriodicalId":7659,"journal":{"name":"American journal of human genetics","volume":"25 1","pages":""},"PeriodicalIF":9.8,"publicationDate":"2024-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}