Latifeh Azizi, Yasumi Otani, Vasyl V Mykuliak, Benjamin T Goult, Vesa P Hytönen, Paula Turkki
{"title":"Talin-1 variants associated with spontaneous coronary artery dissection (SCAD) highlight how even subtle changes in multi-functional scaffold proteins can manifest in disease.","authors":"Latifeh Azizi, Yasumi Otani, Vasyl V Mykuliak, Benjamin T Goult, Vesa P Hytönen, Paula Turkki","doi":"10.1093/hmg/ddae120","DOIUrl":"10.1093/hmg/ddae120","url":null,"abstract":"<p><p>Variants of talin-1 (TLN1) have recently been linked with spontaneous coronary artery dissection (SCAD) a condition where a tear can form in the wall of a heart artery necessitating immediate medical care. One talin-1 variant, A2013T, has an extensive familial pedigree of SCAD, which led to the screening for, and identification of, further talin-1 variants in SCAD patients. Here we evaluated these variants with commonly used pathogenicity prediction tools and found it challenging to reliably classify SCAD-associated variants, even A2013T where the evidence of a causal role is strong. Using biochemical and cell biological methods, we show that SCAD-associated variants in talin-1, which would typically be classified as non-pathogenic, still cause a measurable impact on protein structure and cell behaviour, including cell movement and wound healing capacity. Together, this indicates that even subtle variants in central mechanosensitive adapter proteins, can give rise to significant health impacts at the individual level, suggesting the need for a possible re-evaluation of the scoring criteria for pathogenicity prediction for talin variants.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chaojie Li, Kan Wang, Jian Fang, Lin Qin, Qiong Ling, Yu Yu
{"title":"TRIM25 activates Wnt/β-catenin signalling by destabilising MAT2A mRNA to drive thoracic aortic aneurysm development.","authors":"Chaojie Li, Kan Wang, Jian Fang, Lin Qin, Qiong Ling, Yu Yu","doi":"10.1093/hmg/ddae122","DOIUrl":"10.1093/hmg/ddae122","url":null,"abstract":"<p><p>This study explored the roles of methionine adenosyltransferase 2A (MAT2A) and tripartite motif containing 25 (TRIM25) in the progression of thoracic aortic aneurysm (TAA). The TAA model was established based on the β-aminopropionitrile method. The effects of MAT2A on thoracic aortic lesions and molecular levels were analyzed by several pathological staining assays (hematoxylin-eosin, Verhoeff-Van Gieson, TUNEL) and molecular biology experiments (qRT-PCR, Western blot). Angiotensin II (Ang-II) was used to induce injury in vascular smooth muscle cells (VSMCs) in vitro. The effects of MAT2A, shMAT2A, shTRIM25 and/or Wnt inhibitor (IWR-1) on the viability, apoptosis and protein expressions of VSMCs were examined by CCK-8, Annexin V-FITC/PI and Western blot assays. In TAA mice, overexpression of MAT2A alleviated thoracic aortic injury, inhibited the aberrant expressions of aortic contractile proteins and dedifferentiation markers, and blocked the activation of Wnt/β-catenin pathway. In Ang-II-induced VSMCs, up-regulation of MAT2A increased cellular activity and repressed the expression of β-catenin protein. TRIM25 knockdown promoted activity of VSMCs, inhibited apoptosis, and blocked the Wnt/β-catenin pathway activation by binding to MAT2A. IWR-1 partially counteracted the regulatory effects of shMAT2A. Collectively, TRIM25 destabilises the mRNA of MAT2A to activate Wnt/β-catenin signaling and ultimately exacerbate TAA injury.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142106929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breyanna L Cavanaugh, Michelle L Milstein, R Casey Boucher, Sharon X Tan, Mario W Hanna, Adam Seidel, Rikard Frederiksen, Thomas L Saunders, Alapakkam P Sampath, Kenneth P Mitton, Dao-Qi Zhang, Andrew F X Goldberg
{"title":"A new mouse model for PRPH2 pattern dystrophy exhibits functional compensation prior and subsequent to retinal degeneration.","authors":"Breyanna L Cavanaugh, Michelle L Milstein, R Casey Boucher, Sharon X Tan, Mario W Hanna, Adam Seidel, Rikard Frederiksen, Thomas L Saunders, Alapakkam P Sampath, Kenneth P Mitton, Dao-Qi Zhang, Andrew F X Goldberg","doi":"10.1093/hmg/ddae128","DOIUrl":"10.1093/hmg/ddae128","url":null,"abstract":"<p><p>Mutations in PRPH2 are a relatively common cause of sight-robbing inherited retinal degenerations (IRDs). Peripherin-2 (PRPH2) is a photoreceptor-specific tetraspanin protein that structures the disk rim membranes of rod and cone outer segment (OS) organelles, and is required for OS morphogenesis. PRPH2 is noteworthy for its broad spectrum of disease phenotypes; both inter- and intra-familial heterogeneity have been widely observed and this variability in disease expression and penetrance confounds efforts to understand genotype-phenotype correlations and pathophysiology. Here we report the generation and initial characterization of a gene-edited animal model for PRPH2 disease associated with a nonsense mutation (c.1095:C>A, p.Y285X), which is predicted to truncate the peripherin-2 C-terminal domain. Young (P21) Prph2Y285X/WT mice developed near-normal photoreceptor numbers; however, OS membrane architecture was disrupted, OS protein levels were reduced, and in vivo and ex vivo electroretinography (ERG) analyses found that rod and cone photoreceptor function were each severely reduced. Interestingly, ERG studies also revealed that rod-mediated downstream signaling (b-waves) were functionally compensated in the young animals. This resiliency in retinal function was retained at P90, by which time substantial IRD-related photoreceptor loss had occurred. Altogether, the current studies validate a new mouse model for investigating PRPH2 disease pathophysiology, and demonstrate that rod and cone photoreceptor function and structure are each directly and substantially impaired by the Y285X mutation. They also reveal that Prph2 mutations can induce a functional compensation that resembles homeostatic plasticity, which can stabilize rod-derived signaling, and potentially dampen retinal dysfunction during some PRPH2-associated IRDs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alternative polyadenylation shapes the molecular and clinical features of lung adenocarcinoma.","authors":"Yipeng Gao, Vikram R Shaw, Christopher I Amos","doi":"10.1093/hmg/ddae150","DOIUrl":"https://doi.org/10.1093/hmg/ddae150","url":null,"abstract":"<p><p>Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation that affects mRNA stability, localization and translation efficiency. Previous pan-cancer studies have revealed that APA is frequently disrupted in cancer and is associated with patient outcomes. Yet, little is known about cancer type-specific APA alterations. Here, we integrated RNA-sequencing data from a Korean cohort (GEO: GSE40419) and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA alterations in lung adenocarcinomas (LUADs). Comparing expression levels of core genes involved in polyadenylation, we find that overall, the set of 28 of 31 genes are upregulated, with CSTF2 particularly upregulated. We observed broad and recurrent APA changes in LUAD growth-promoting genes. In addition, we find enrichment of APA events in genes associated with known LUAD pathways and an increased heterogeneity in polyadenylation (polyA) site usage of proliferation-associated genes. Upon further investigation, we report smoking-specific APA changes are also highly relevant to LUAD development. Overall, our in-depth analysis reveals APA as an important driver for the molecular and clinical features of lung adenocarcinoma.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Logan M Morrison, Haoran Huang, Hillary P Handler, Min Fu, Deborah M Jones, David D Bushart, Samuel S Pappas, Harry T Orr, Vikram G Shakkottai
{"title":"Increased intrinsic membrane excitability is associated with olivary hypertrophy in spinocerebellar ataxia type 1.","authors":"Logan M Morrison, Haoran Huang, Hillary P Handler, Min Fu, Deborah M Jones, David D Bushart, Samuel S Pappas, Harry T Orr, Vikram G Shakkottai","doi":"10.1093/hmg/ddae146","DOIUrl":"10.1093/hmg/ddae146","url":null,"abstract":"<p><p>One of the characteristic regions of brainstem degeneration across multiple spinocerebellar ataxias (SCAs) is the inferior olive (IO), a medullary nucleus that plays a key role in motor learning. The vulnerability of IO neurons remains a poorly-understood area of SCA pathology. In this work, we address this by evaluating IO disease in SCA1, a prototypic inherited olivopontocerebellar atrophy, using the genetically-precise SCA1 knock-in (SCA1-KI) mouse. We find that these mice exhibit olivary hypertrophy, a phenotype reminiscent of a degenerative disorder known as hypertrophic olivary degeneration (HOD). Similar to early stages of HOD, SCA1-KI IO neurons display early dendritic lengthening and later somatic expansion without frank cell loss. Though HOD is known to be caused by brainstem lesions that disrupt IO inhibitory innervation, we observe no loss of inhibitory terminals in the SCA1-KI IO. Additionally, we find that a separate mouse model of SCA1 in which mutant ATXN1 is expressed solely in cerebellar Purkinje cells shows no evidence of olivary hypertrophy. Patch-clamp recordings from brainstem slices indicate that SCA1-KI IO neurons are hyperexcitable, generating spike trains in response to membrane depolarization. Transcriptome analysis further reveals reduced medullary expression of ion channels responsible for IO neuron spike afterhyperpolarization (AHP)-a result that appears to have a functional consequence, as SCA1-KI IO neuron spikes exhibit a diminished AHP. These findings suggest that expression of mutant ATXN1 in IO neurons results in an HOD-like olivary hypertrophy, in association with increased intrinsic membrane excitability and ion channel transcriptional dysregulation.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Reduced levels of MRE11 cause disease phenotypes distinct from ataxia telangiectasia-like disorder.","authors":"","doi":"10.1093/hmg/ddae145","DOIUrl":"https://doi.org/10.1093/hmg/ddae145","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Menachem V K Sarusie, Cecilia Rönnbäck, Cathrine Jespersgaard, Sif Baungaard, Yeasmeen Ali, Line Kessel, Søren T Christensen, Karen Brøndum-Nielsen, Kjeld Møllgård, Thomas Rosenberg, Lars A Larsen, Karen Grønskov
{"title":"A novel GFAP frameshift variant identified in a family with optico-retinal dysplasia and vision impairment.","authors":"Menachem V K Sarusie, Cecilia Rönnbäck, Cathrine Jespersgaard, Sif Baungaard, Yeasmeen Ali, Line Kessel, Søren T Christensen, Karen Brøndum-Nielsen, Kjeld Møllgård, Thomas Rosenberg, Lars A Larsen, Karen Grønskov","doi":"10.1093/hmg/ddae134","DOIUrl":"https://doi.org/10.1093/hmg/ddae134","url":null,"abstract":"<p><p>Gain-of-function variants in GFAP leads to protein aggregation and is the cause of the severe neurodegenerative disorder Alexander Disease (AxD), while loss of GFAP function has been considered benign. Here, we investigated a six-generation family, where multiple individuals presented with gliosis of the optic nerve head and visual impairment. Whole genome sequencing (WGS) revealed a frameshift variant in GFAP (c.928dup, p.(Met310Asnfs*113)) segregating with disease. Analysis of human embryonic tissues revealed strong expression of GFAP in retinal neural progenitors. A zebrafish model verified that c.928dup does not result in extensive GFAP protein aggregation and zebrafish gfap loss-of-function mutants showed vision impairment and retinal dysplasia, characterized by a significant loss of Müller glia cells and photoreceptor cells. Our findings show how different mutational mechanisms can cause diverging phenotypes and reveal a novel function of GFAP in vertebrate eye development.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mao Luo, Ziqi Jiang, Ping Wang, Yangmei Chen, Aijun Chen, Bin Wei
{"title":"HDAC1-mediated regulation of KDM1A in pemphigus vulgaris: unlocking mechanisms on ERK pathway activation and cohesion loss.","authors":"Mao Luo, Ziqi Jiang, Ping Wang, Yangmei Chen, Aijun Chen, Bin Wei","doi":"10.1093/hmg/ddae090","DOIUrl":"https://doi.org/10.1093/hmg/ddae090","url":null,"abstract":"<p><p>Pemphigus vulgaris (PV) is an autoimmune skin disorder characterized by the loss of cell cohesion, with the histone deacetylase 1 (HDAC1) and lysine demethylase 1A (KDM1A) playing critical roles in its pathogenesis. This study aimed to elucidate the molecular mechanisms behind PV, focusing on the function of HDAC1 and KDM1A in disease onset and progression. Based on in vitro and in vivo PV models, we observed a significant increase in HDAC1 mRNA and protein levels in skin tissues of PV patients. Inhibition of HDAC1 ameliorated cell damage and reduced the loss of cell cohesion in human epidermal keratinocytes (HEKs) induced by PV-IgG. Our findings suggest that HDAC1 regulates KDM1A expression through deacetylation, with a notable deficiency in KDM1A expression in PV. Overexpression of KDM1A mitigated cell damage and cohesion loss. The extracellular signal-regulated kinase (ERK) pathway serves as a downstream executor of the HDAC1/KDM1A axis. Inhibiting HDAC1 and increasing KDM1A expression suppressed ERK phosphorylation, reducing PV-related apoptosis. These insights provide a new perspective on treating PV, highlighting the therapeutic potential of targeting HDAC1 expression. The regulatory mechanism of the HDAC1/KDM1A/ERK axis offers crucial clues for understanding PV pathogenesis and developing novel treatments.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuqing Huang, Yiru A Wang, Lisa van Sluijs, Demi H J Vogels, Yuzhi Chen, Vivian I P Tegelbeckers, Steven Schoonderwoerd, Joost A G Riksen, Jan E Kammenga, Simon C Harvey, Mark G Sterken
{"title":"eQTL mapping in transgenic alpha-synuclein carrying Caenorhabditis elegans recombinant inbred lines.","authors":"Yuqing Huang, Yiru A Wang, Lisa van Sluijs, Demi H J Vogels, Yuzhi Chen, Vivian I P Tegelbeckers, Steven Schoonderwoerd, Joost A G Riksen, Jan E Kammenga, Simon C Harvey, Mark G Sterken","doi":"10.1093/hmg/ddae148","DOIUrl":"https://doi.org/10.1093/hmg/ddae148","url":null,"abstract":"<p><p>Protein aggregation of α-synuclein (αS) is a genetic and neuropathological hallmark of Parkinson's disease (PD). Studies in the model nematode Caenorhabditis elegans suggested that variation of αS aggregation depends on the genetic background. However, which genes and genetic modifiers underlie individual differences in αS pathology remains unknown. To study the genotypic-phenotypic relationship of αS aggregation, we constructed a Recombinant Inbred Line (RIL) panel derived from a cross between genetically divergent strains C. elegans NL5901 and SCH4856, both harboring the human αS gene. As a first step to discover genetic modifiers 70 αS-RILs were measured for whole-genome gene expression and expression quantitative locus analysis (eQTL) were mapped. We detected multiple eQTL hot-spots, many of which were located on Chromosome V. To confirm a causal locus, we developed Introgression Lines (ILs) that contain SCH4856 introgressions on Chromosome V in an NL5901 background. We detected 74 genes with an interactive effect between αS and the genetic background, including the human p38 MAPK homologue pmk-1 that has previously been associated with PD. Together, we present a unique αS-RIL panel for defining effects of natural genetic variation on αS pathology, which contributes to finding genetic modifiers of PD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142499408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alexander J Hull, Magda L Atilano, Jenny Hallqvist, Wendy Heywood, Kerri J Kinghorn
{"title":"Ceramide lowering rescues respiratory defects in a Drosophila model of acid sphingomyelinase deficiency.","authors":"Alexander J Hull, Magda L Atilano, Jenny Hallqvist, Wendy Heywood, Kerri J Kinghorn","doi":"10.1093/hmg/ddae143","DOIUrl":"https://doi.org/10.1093/hmg/ddae143","url":null,"abstract":"<p><p>Types A and B Niemann-Pick disease (NPD) are inherited multisystem lysosomal storage disorders due to mutations in the SMPD1 gene. Respiratory dysfunction is a key hallmark of NPD, yet the mechanism for this is underexplored. SMPD1 encodes acid sphingomyelinase (ASM), which hydrolyses sphingomyelin to ceramide and phosphocholine. Here, we present a Drosophila model of ASM loss-of-function, lacking the fly orthologue of SMPD1, dASM, modelling several aspects of the respiratory pathology of NPD. dASM is expressed in the late-embryonic fly respiratory network, the trachea, and is secreted into the tracheal lumen. Loss of dASM results in embryonic lethality, and the tracheal lumen fails to fill normally with gas prior to eclosion. We demonstrate that the endocytic clearance of luminal constituents prior to gas-filling is defective in dASM mutants, and is coincident with autophagic, but not lysosomal defects, in late stage embryonic trachea. Finally, we show that although bulk sphingolipids are unchanged, dietary loss of lipids in combination with genetic and pharmacological block of ceramide synthesis rescues the airway gas-filling defects. We highlight myriocin as a potential therapeutic drug for the treatment of the developmental respiratory defects associated with ASM deficiency, and present a new NPD model amenable to genetic and pharmacological screens.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}