HGG Advances最新文献

筛选
英文 中文
An ADPRS variant disrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure. ADPRS变体会破坏神经变性和呼吸衰竭患儿体内ARH3的稳定性和亚细胞定位。
IF 3.3
HGG Advances Pub Date : 2024-11-22 DOI: 10.1016/j.xhgg.2024.100386
Maxwell Bannister, Sarah Bray, Anjali Aggarwal, Charles Billington, Hai Dang Nguyen
{"title":"An ADPRS variant disrupts ARH3 stability and subcellular localization in children with neurodegeneration and respiratory failure.","authors":"Maxwell Bannister, Sarah Bray, Anjali Aggarwal, Charles Billington, Hai Dang Nguyen","doi":"10.1016/j.xhgg.2024.100386","DOIUrl":"10.1016/j.xhgg.2024.100386","url":null,"abstract":"<p><p>ADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. In this study, genetic testing via exome sequencing was used to identify the underlying disease in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. This identified a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3, confirming the diagnosis of childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS) in these 2 children. Mechanistically, the ARH3<sup>H182R</sup> variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and subsequently, reduced protein expression. The ARH3<sup>H182R</sup> mutant additionally fails to localize to the nucleus, which further resulted in accumulated mono-ADP ribosylated species in cells. The children's clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100386"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A multi-ancestry genome-wide association study identifies novel candidate loci in the RARB gene associated with hypertensive disorders of pregnancy. 一项多家系全基因组关联研究发现了与妊娠高血压疾病相关的 RARB 基因新候选位点。
IF 3.3
HGG Advances Pub Date : 2024-11-22 DOI: 10.1016/j.xhgg.2024.100385
Jasmine A Mack, Adam Burkholder, Farida S Akhtari, John S House, Ulla Sovio, Gordon C S Smith, Charles P Schmitt, David C Fargo, Janet E Hall, Alison A Motsinger-Reif
{"title":"A multi-ancestry genome-wide association study identifies novel candidate loci in the RARB gene associated with hypertensive disorders of pregnancy.","authors":"Jasmine A Mack, Adam Burkholder, Farida S Akhtari, John S House, Ulla Sovio, Gordon C S Smith, Charles P Schmitt, David C Fargo, Janet E Hall, Alison A Motsinger-Reif","doi":"10.1016/j.xhgg.2024.100385","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100385","url":null,"abstract":"<p><p>Genetic factors related to pregnancy-related traits are understudied, especially in ancestrally diverse cohorts. To assess maternal contributions to hypertensive disorders of pregnancy (HDP, we performed a multi-ancestry genome-wide association study (GWAS) of HDP in data from the North Carolina-based Personalized Environment and Genes Study (PEGS) cohort with validation in the UK Biobank (UKBB). The GWAS revealed two maternal loci associated with HDP at the genome-wide significance level. The lead independent variants were rs114954125 on chromosome 2 (near LRP1B; OR (95% CI): 2.96 (2.02,4.34); P=2.82 x 10<sup>-8</sup>) and rs61176331 on chromosome 3 (on RARB; OR (95% CI): 3.08 (2.12,4.48); P=3.52 x 10<sup>-9</sup>). We validated the associations near RARB with a meta-analysis of PEGS and the UK Biobank. We also identified cis-eQTLs in the candidate region associated with decreased RARB expression in macrophage cells exposed to Salmonella. Chromatin mapping in FUMA identified a significant interaction within chromosome 3's enhancer and open chromatin regions, with strong effects observed for RARB and H3P10 gene regulation in mesendoderm cells, mesenchymal stem cells, and trophoblast-like stem cells. We applied existing polygenic scores (PGS) for preeclampsia and gestational hypertension and found the scores were significantly associated with HDP in PEGS. The findings demonstrate the power of multi-ancestry studies for genetic discovery and highlight the relationship between immune response, regulation, and HDP and the utility of PGS for risk prediction.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100385"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Germline De Novo Alterations of RUNX1T1 in Individuals with Neurodevelopmental and Congenital Anomalies. 神经发育异常和先天性畸形患者的 RUNX1T1 基因新变异
IF 3.3
HGG Advances Pub Date : 2024-11-19 DOI: 10.1016/j.xhgg.2024.100384
Erfan Aref-Eshghi, Katherine J Anderson, Lauren Boulay, Kathleen Brown, Jessica Duis, Christine A Giummo, Jessica Ogawa, Deanna Alexis Carere, Elizabeth A Normand, Yaping Qian, Kirsty McWalter, Erin Torti
{"title":"Germline De Novo Alterations of RUNX1T1 in Individuals with Neurodevelopmental and Congenital Anomalies.","authors":"Erfan Aref-Eshghi, Katherine J Anderson, Lauren Boulay, Kathleen Brown, Jessica Duis, Christine A Giummo, Jessica Ogawa, Deanna Alexis Carere, Elizabeth A Normand, Yaping Qian, Kirsty McWalter, Erin Torti","doi":"10.1016/j.xhgg.2024.100384","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100384","url":null,"abstract":"<p><p>RUNX1T1 (ETO) encodes a transcription regulator for hematopoietic genes and is well-known for its involvement in hematologic malignancies, particularly acute myeloid leukemia (AML). However, its role in congenital disease is less understood. This study provides detailed clinical and molecular information on three cases exhibiting neurodevelopmental and congenital anomalies with germline de novo alterations in RUNX1T1. One case features a de novo nonsense variant in the 5' region of the gene (p.Gln36Ter), while the other two harbor de novo missense variants in the C-terminus end (p.Gly412Arg and p.His521Tyr). Common features across cases include craniofacial dysmorphism and neurodevelopmental issues including developmental delay, learning disabilities, attention deficit hyperactivity disorder, and autism. This study, in conjunction with previously reported germline disruptions of RUNX1T1, provides evidence supporting the role of germline RUNX1T1 variation in human congenital neurodevelopmental disorders.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100384"},"PeriodicalIF":3.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Proteome-Wide Association Studies for Blood Lipids and Comparison with Transcriptome-Wide Association Studies. 全蛋白质组血脂关联研究及与全转录组关联研究的比较
IF 3.3
HGG Advances Pub Date : 2024-11-13 DOI: 10.1016/j.xhgg.2024.100383
Daiwei Zhang, Boran Gao, Qidi Feng, Ani Manichaikul, Gina M Peloso, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Stacey Gabriel, Namrata Gupta, Joshua D Smith, Francois Aguet, Kristin G Ardlie, Thomas W Blackwell, Robert E Gerszten, Stephen S Rich, Jerome I Rotter, Laura J Scott, Xiang Zhou, Seunggeun Lee
{"title":"Proteome-Wide Association Studies for Blood Lipids and Comparison with Transcriptome-Wide Association Studies.","authors":"Daiwei Zhang, Boran Gao, Qidi Feng, Ani Manichaikul, Gina M Peloso, Russell P Tracy, Peter Durda, Kent D Taylor, Yongmei Liu, W Craig Johnson, Stacey Gabriel, Namrata Gupta, Joshua D Smith, Francois Aguet, Kristin G Ardlie, Thomas W Blackwell, Robert E Gerszten, Stephen S Rich, Jerome I Rotter, Laura J Scott, Xiang Zhou, Seunggeun Lee","doi":"10.1016/j.xhgg.2024.100383","DOIUrl":"10.1016/j.xhgg.2024.100383","url":null,"abstract":"<p><p>Blood lipid traits are treatable and heritable risk factors for heart disease, a leading cause of mortality worldwide. Although genome-wide association studies (GWAS) have discovered hundreds of variants associated with lipids in humans, most of the causal mechanisms of lipids remain unknown. To better understand the biological processes underlying lipid metabolism, we investigated the associations of plasma protein levels with total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL) in blood. We trained protein prediction models based on samples in the Multi-Ethnic Study of Atherosclerosis (MESA) and applied them to conduct proteome-wide association studies (PWAS) for lipids using the Global Lipids Genetics Consortium (GLGC) data. Of the 749 proteins tested, 42 were significantly associated with at least one lipid trait. Furthermore, we performed transcriptome-wide association studies (TWAS) for lipids using 9,714 gene expression prediction models trained on samples from peripheral blood mononuclear cells (PBMCs) in MESA and 49 tissues in the Genotype-Tissue Expression (GTEx) project. We found that although PWAS and TWAS can show different directions of associations in an individual gene, 40 out of 49 tissues showed a positive correlation between PWAS and TWAS signed p-values across all the genes, which suggests a high-level consistency between proteome-lipid associations and transcriptome-lipid associations.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100383"},"PeriodicalIF":3.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature. CUL3相关神经发育障碍:20个新个体的临床表型及潜在表型相关表征的鉴定。
IF 3.3
HGG Advances Pub Date : 2024-11-04 DOI: 10.1016/j.xhgg.2024.100380
Liselot van der Laan, Ananília Silva, Lotte Kleinendorst, Kathleen Rooney, Sadegheh Haghshenas, Peter Lauffer, Yasemin Alanay, Pratibha Bhai, Alfredo Brusco, Sonja de Munnik, Bert B A de Vries, Angelica Delgado Vega, Marc Engelen, Johanna C Herkert, Ron Hochstenbach, Saskia Hopman, Sarina G Kant, Ryutaro Kira, Mitsuhiro Kato, Boris Keren, Hester Y Kroes, Michael A Levy, Ngu Lock-Hock, Saskia M Maas, Grazia M S Mancini, Carlo Marcelis, Naomichi Matsumoto, Takeshi Mizuguchi, Alessandro Mussa, Cyril Mignot, Anu Närhi, Ann Nordgren, Rolph Pfundt, Abeltje M Polstra, Slavica Trajkova, Yolande van Bever, Marie José van den Boogaard, Jasper J van der Smagt, Tahsin Stefan Barakat, Mariëlle Alders, Marcel M A M Mannens, Bekim Sadikovic, Mieke M van Haelst, Peter Henneman
{"title":"CUL3-related neurodevelopmental disorder: Clinical phenotype of 20 new individuals and identification of a potential phenotype-associated episignature.","authors":"Liselot van der Laan, Ananília Silva, Lotte Kleinendorst, Kathleen Rooney, Sadegheh Haghshenas, Peter Lauffer, Yasemin Alanay, Pratibha Bhai, Alfredo Brusco, Sonja de Munnik, Bert B A de Vries, Angelica Delgado Vega, Marc Engelen, Johanna C Herkert, Ron Hochstenbach, Saskia Hopman, Sarina G Kant, Ryutaro Kira, Mitsuhiro Kato, Boris Keren, Hester Y Kroes, Michael A Levy, Ngu Lock-Hock, Saskia M Maas, Grazia M S Mancini, Carlo Marcelis, Naomichi Matsumoto, Takeshi Mizuguchi, Alessandro Mussa, Cyril Mignot, Anu Närhi, Ann Nordgren, Rolph Pfundt, Abeltje M Polstra, Slavica Trajkova, Yolande van Bever, Marie José van den Boogaard, Jasper J van der Smagt, Tahsin Stefan Barakat, Mariëlle Alders, Marcel M A M Mannens, Bekim Sadikovic, Mieke M van Haelst, Peter Henneman","doi":"10.1016/j.xhgg.2024.100380","DOIUrl":"10.1016/j.xhgg.2024.100380","url":null,"abstract":"<p><p>Neurodevelopmental disorder with or without autism or seizures (NEDAUS) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features, and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase) haploinsufficiency. We collected clinical and molecular data from 26 individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including 20 previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge of the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we performed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying 20 new individuals and confirming five previously reported cases of NEDAUS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100380"},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Chronic overlapping pain conditions and nociplastic pain. 慢性重叠性疼痛病症和 Nociplastic 疼痛。
IF 3.3
HGG Advances Pub Date : 2024-11-04 DOI: 10.1016/j.xhgg.2024.100381
Keira J A Johnston, Rebecca Signer, Laura M Huckins
{"title":"Chronic overlapping pain conditions and nociplastic pain.","authors":"Keira J A Johnston, Rebecca Signer, Laura M Huckins","doi":"10.1016/j.xhgg.2024.100381","DOIUrl":"10.1016/j.xhgg.2024.100381","url":null,"abstract":"<p><p>Chronic overlapping pain conditions (COPCs) are a subset of chronic pain conditions commonly comorbid with one another and more prevalent in women and individuals assigned female at birth (AFAB). Pain experience in these conditions may better fit with a new mechanistic pain descriptor, nociplastic pain, and nociplastic pain may represent a shared underlying factor among COPCs. We applied GenomicSEM common-factor genome-wide association study (GWAS) and multivariate transcriptome-wide association (TWAS) analyses to existing GWAS output for six COPCs in order to find genetic variation associated with nociplastic pain, followed by genetic correlation (linkage disequilibrium score regression), gene set, and tissue enrichment analyses. We found 24 independent single nucleotide polymorphisms (SNPs), and 127 unique genes significantly associated with nociplastic pain, and showed nociplastic pain to be a polygenic trait with significant SNP heritability. We found significant genetic overlap between multisite chronic pain and nociplastic pain, and to a smaller extent with rheumatoid arthritis and a neuropathic pain phenotype. Tissue enrichment analyses highlighted cardiac and thyroid tissue, and gene set enrichment analyses emphasized potential shared mechanisms in cognitive, personality, and metabolic traits and nociplastic pain along with distinct pathology in migraine and headache. We used a well-powered network approach to investigate nociplastic pain using existing COPC GWAS output, and show nociplastic pain to be a complex, heritable trait, in addition to contributing to understanding of potential mechanisms in development of nociplastic pain.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100381"},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome. 扩展CSNK2A1相关Okur-Chung神经发育综合征的表型谱。
IF 3.3
HGG Advances Pub Date : 2024-11-04 DOI: 10.1016/j.xhgg.2024.100379
Swetha Ramadesikan, Iftekhar A Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A Varga, Umamaheswaran Gurusamy, Matthew T Pastore, Emily R Sites, Murugu Manickam, Dennis W Bartholomew, Jesse M Hunter, Peter White, Richard K Wilson, Rolf W Stottmann, Daniel C Koboldt
{"title":"Expanding the phenotypic spectrum of CSNK2A1-associated Okur-Chung neurodevelopmental syndrome.","authors":"Swetha Ramadesikan, Iftekhar A Showpnil, Mohammad Marhabaie, Allison Daley, Elizabeth A Varga, Umamaheswaran Gurusamy, Matthew T Pastore, Emily R Sites, Murugu Manickam, Dennis W Bartholomew, Jesse M Hunter, Peter White, Richard K Wilson, Rolf W Stottmann, Daniel C Koboldt","doi":"10.1016/j.xhgg.2024.100379","DOIUrl":"10.1016/j.xhgg.2024.100379","url":null,"abstract":"<p><p>De novo variants in CSNK2A1 cause autosomal dominant Okur-Chung neurodevelopmental syndrome (OCNDS). OCNDS has an evolving clinical phenotype predominantly characterized by intellectual disability, global delays, dysmorphic features, and immunological manifestations. Microcephaly, defined as a small head circumference, is not widely recognized as a classical clinical presentation. Here, we describe four individuals from three unrelated families who shared several clinical features characteristic of an underlying syndromic neurodevelopmental condition. Trio clinical exome and research genome sequencing revealed that all affected individuals had heterozygous pathogenic missense variants in CSNK2A1. Two variants (c.468T>A p.Asp156Glu and c.149A>G p.Tyr50Cys) were de novo and previously reported, but the third variant (c.137G>T p.Gly46Val) is novel and segregated in two affected individuals in a family. This adds to growing evidence of inherited disease-causing variants in CSNK2A1, an observation reported only twice previously. A detailed phenotypic analysis of our cohort together with those individuals reported in the literature revealed that OCNDS individuals, on average, have a smaller head circumference with one-third presenting with microcephaly. We also show that the incidence of microcephaly is significantly correlated with the location of the variant in the encoded protein. Our findings suggest that small head circumference is a common but under-recognized feature of OCNDS, which may not be apparent at birth.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100379"},"PeriodicalIF":3.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Letter to the Editor: Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection. 致编辑的信:经典HLA基因与无症状SARS-CoV-2感染之间缺乏关联。
IF 3.3
HGG Advances Pub Date : 2024-11-02 DOI: 10.1016/j.xhgg.2024.100382
Eleanor Karp-Tatham, Callum R O'Neill, Julian C Knight, Alexander J Mentzer, Amanda Y Chong
{"title":"Letter to the Editor: Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection.","authors":"Eleanor Karp-Tatham, Callum R O'Neill, Julian C Knight, Alexander J Mentzer, Amanda Y Chong","doi":"10.1016/j.xhgg.2024.100382","DOIUrl":"https://doi.org/10.1016/j.xhgg.2024.100382","url":null,"abstract":"<p><p>Research into HLA-B*15:01 association with asymptomatic SARS-CoV-2 infection has so far yielded contradicting results. Using the UK Biobank cohort, we found a significant association between HLA-B*15:01 and asymptomatic infection. Our study adds more evidence for the complex role HLA alleles play in SARS-Cov-2 infection severity.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100382"},"PeriodicalIF":3.3,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome. RLIM 特异性活性报告确定了 Tonne-Kalscheuer 综合征的变异致病性。
IF 3.3
HGG Advances Pub Date : 2024-10-31 DOI: 10.1016/j.xhgg.2024.100378
Venkateshwarlu Bandi, Martin Rennie, Intisar Koch, Polly Gill, Oscar D Pacheco, Aaron D Berg, Hong Cui, D Isum Ward, Francisco Bustos
{"title":"RLIM-specific activity reporters define variant pathogenicity in Tonne-Kalscheuer syndrome.","authors":"Venkateshwarlu Bandi, Martin Rennie, Intisar Koch, Polly Gill, Oscar D Pacheco, Aaron D Berg, Hong Cui, D Isum Ward, Francisco Bustos","doi":"10.1016/j.xhgg.2024.100378","DOIUrl":"10.1016/j.xhgg.2024.100378","url":null,"abstract":"<p><p>Tonne-Kalscheuer syndrome (TOKAS; MIM: 300978) is an X-linked recessive disorder with devastating consequences for patients, such as intellectual disability, developmental delay, and multiple congenital abnormalities. TOKAS is associated with hemizygous variants in the RLIM gene, which encodes a RING-type E3 ubiquitin ligase. The current sustained increase in reported RLIM variants of uncertain significance creates an urgent need to develop assays that can screen these variants and experimentally determine their pathogenicity and disease association. Here, we engineered flow cytometry-based RLIM-specific reporters to measure RLIM activity in TOKAS. This paper describes the design and use of RLIM-specific reporters to determine the pathogenicity of a TOKAS RLIM gene variant. Our data demonstrate that RLIM-specific flow cytometry reporters based on either the full length or a degron region of the substrate REX1 measure RLIM activity in cells. Further, we describe the TOKAS variant RLIM p.Asn581Lys and, using reporter assays, determine that it disrupts RLIM catalytic activity. These data reveal how the p.Asn581Lys variant impairs RLIM function and suggests pathogenic mechanisms. The use of RLIM-specific reporters will greatly accelerate the resolution of variants of uncertain significance and disease association in TOKAS.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100378"},"PeriodicalIF":3.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification. 癫痫性脑病与影响 tRNA 修饰的 DALRD3 错义变体有关。
IF 4.3
HGG Advances Pub Date : 2024-10-31 DOI: 10.1016/j.xhgg.2024.100377
Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu
{"title":"Epileptic encephalopathy linked to a DALRD3 missense variant that impairs tRNA modification.","authors":"Kejia Zhang, Katharina Löhner, Henny H Lemmink, Maartje Boon, Jenna M Lentini, Naduni de Silva, Dragony Fu","doi":"10.1016/j.xhgg.2024.100377","DOIUrl":"10.1016/j.xhgg.2024.100377","url":null,"abstract":"<p><p>Epileptic encephalopathies are severe epilepsy syndromes characterized by early onset and progressive cerebral dysfunction. A nonsense variant in the DALR anticodon binding domain containing 3 (DALRD3) gene has been implicated in epileptic encephalopathy, but no other disease-associated variants in DALRD3 have been described. In human cells, the DALRD3 protein forms a complex with the METTL2 methyltransferase to generate the 3-methylcytosine (m3C) modification in specific arginine tRNAs. Here, we identify an individual with a homozygous missense variant in DALRD3 who displays developmental delay, cognitive deficiencies, and multifocal epilepsy. The missense variant substitutes an arginine residue to cysteine (R517C) within the DALR domain of the DALRD3 protein that is required for binding tRNAs. Cells derived from the individual homozygous for the DALRD3-R517C variant exhibit reduced levels of m3C modification in arginine tRNAs, indicating that the R517C variant impairs DALRD3 function. Notably, the DALRD3-R517C protein displays reduced association with METTL2 and loss of interaction with substrate tRNAs. Our results uncover another loss-of-function variant in DALRD3 linked to epileptic encephalopathy disorders. Importantly, these findings underscore DALRD3-dependent tRNA modification as a key contributor to proper brain development and function.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":" ","pages":"100377"},"PeriodicalIF":4.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信