PLoS Genetics最新文献

{"title":"F-box protein Fbx23 acts as a transcriptional coactivator to recognize and activate transcription factor Ace1.","authors":"Zhongjiao Liu, Kexuan Ma, Panpan Zhang, Siqi Zhang, Xin Song, Yuqi Qin","doi":"10.1371/journal.pgen.1011539","DOIUrl":"10.1371/journal.pgen.1011539","url":null,"abstract":"<p><p>Protein ubiquitination is usually coupled with proteasomal degradation and is crucial in regulating protein quality. The E3 ubiquitin-protein ligase SCF (Skp1-Cullin-F-box) complex directly recognizes the target substrate via interaction between the F-box protein and the substrate. F-box protein is the determinant of substrate specificity. The limited number of identified ubiquitin ligase-substrate pairs is a major bottleneck in the ubiquitination field. Penicillium oxalicum contains many transcription factors, such as BrlA, CreA, XlnR, and Ace1, conserved in filamentous fungi that regulate the fungal development and transcription of (hemi)cellulase genes. Transcription factor Ace1 (also known as SltA) positively correlated with fungal growth and conidiation and negatively correlated with the expression of (hemi)cellulase genes. A ubiquitin ligase-substrate pair, SCFFbx23-Ace1, is identified in P. oxalicum. Most of PoFbx23 is present in free form within the nucleus. A small portion of PoFbx23 associates with Skp1 to form PoFbx23-Skp1 heterodimer or assembles with the three invariable core components (Skp1, Cul1, and Rbx1) of SCF to form the SCFFbx23 complex. Under glucose signal, PoFbx23 absence (Δfbx23) results in decreased transcription levels of the brlA gene which encodes the master regulator for asexual development and six spore pigmentation genes (abrB→abrA→aygB→arpA→arpB→albA) which encode the proteins in the dihydroxynaphthalene-melanin pathway, along with impaired conidiation. Under cellulose signal, transcription levels of (hemi)cellulase genes in the Δfbx23 mutant are significantly upregulated. When PoFbx23 is present, PoAce1 exists as a full-length version and several low-molecular-weight degraded versions. PoAce1 has polyubiquitin modification. Deleting the Pofbx23 gene does not affect Poace1 gene transcription but results in the remarkable accumulation of all versions of the PoAce1 protein. Accumulated PoAce1 protein is a dysfunctional form that no longer binds promoters of the target gene, including the cellulase genes cbh1 and eg1, the hemicellulase gene xyn11A, and the pigmentation-related gene abrB. PoFbx23 acts as a transcriptional coactivator, recognizing and activating PoAce1, allowing the latter to regulate the transcription of target genes with different effects (activating or repressing) under different signals.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011539"},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11750091/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014666","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":"Sequence specificity of an essential nuclear localization sequence in Mcm3.","authors":"Ziyi Wang, Yun Jing Zhang, Qian-Yi Zhang, Kate Bilsborrow, Matthew Leslie, Raymond T Suhandynata, Huilin Zhou","doi":"10.1371/journal.pgen.1011499","DOIUrl":"10.1371/journal.pgen.1011499","url":null,"abstract":"<p><p>Proteins with nuclear localization sequences (NLSs) are directed into the cell nucleus through interactions between the NLS and importin proteins. NLSs are generally short motifs rich in basic amino acids; however, identifying NLSs can be challenging due to the lack of a universally conserved sequence. In this study, we characterized the sequence specificity of an essential and conserved NLS in Mcm3, a subunit of the replicative DNA helicase. Through mutagenesis and AlphaFold 3 (AF3) modeling, we demonstrate that the precise positioning of basic residues within the NLS is critical for nuclear transport of Mcm3 through optimal interactions with importin. Disrupting these interactions impairs the nuclear import of Mcm3, resulting in defective chromatin loading of the MCM complex and poor cell growth. Our results provide a structure-guided framework for predicting and analyzing monopartite NLSs, which, despite lacking a single consensus sequence, retain key characteristics shared between the NLSs of Mcm3 and the SV40 large T antigen.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011499"},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014680","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":"SEM-2/SoxC regulates multiple aspects of C. elegans postembryonic mesoderm development.","authors":"Marissa Baccas, Vanathi Ganesan, Amy Leung, Lucas R Pineiro, Alexandra N McKillop, Jun Liu","doi":"10.1371/journal.pgen.1011361","DOIUrl":"10.1371/journal.pgen.1011361","url":null,"abstract":"<p><p>Development of multicellular organisms requires well-orchestrated interplay between cell-intrinsic transcription factors and cell-cell signaling. One set of highly conserved transcription factors that plays diverse roles in development is the SoxC group. C. elegans contains a sole SoxC protein, SEM-2. SEM-2 is essential for embryonic development, and for specifying the sex myoblast (SM) fate in the postembryonic mesoderm, the M lineage. We have identified a novel partial loss-of-function sem-2 allele that has a proline to serine change in the C-terminal tail of the highly conserved DNA-binding domain. Detailed analyses of mutant animals harboring this point mutation uncovered new functions of SEM-2 in the M lineage. First, SEM-2 functions antagonistically with LET-381, the sole C. elegans FoxF/C forkhead transcription factor, to regulate dorsoventral patterning of the M lineage. Second, in addition to specifying the SM fate, SEM-2 is essential for the proliferation and diversification of the SM lineage. Finally, SEM-2 appears to directly regulate the expression of hlh-8, which encodes a basic helix-loop-helix Twist transcription factor and plays critical roles in proper patterning of the M lineage. Our data, along with previous studies, suggest an evolutionarily conserved relationship between SoxC and Twist proteins. Furthermore, our work identified new interactions in the gene regulatory network (GRN) underlying C. elegans postembryonic development and adds to the general understanding of the structure-function relationship of SoxC proteins.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011361"},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014679","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":"Characterizing the regulatory effects of H2A.Z and SWR1-C on gene expression during hydroxyurea exposure in Saccharomyces cerevisiae.","authors":"Hilary T Brewis, Peter C Stirling, Michael S Kobor","doi":"10.1371/journal.pgen.1011566","DOIUrl":"10.1371/journal.pgen.1011566","url":null,"abstract":"<p><p>Chromatin structure and DNA accessibility are partly modulated by the incorporation of histone variants. H2A.Z, encoded by the non-essential HTZ1 gene in S. cerevisiae, is an evolutionarily conserved H2A histone variant that is predominantly incorporated at transcription start sites by the SWR1-complex (SWR1-C). While H2A.Z has often been implicated in transcription regulation, htz1Δ mutants exhibit minimal changes in gene expression compared to wild-type. However, given that growth defects of htz1Δ mutants are alleviated by simultaneous deletion of SWR1-C subunits, previous work examining the role of H2A.Z in gene expression regulation may be confounded by deleterious activity caused by SWR1-C when missing its H2A.Z substrate (apo-SWR1-C). Furthermore, as H2A.Z mutants only display significant growth defects in genotoxic stress conditions, a more substantive role for H2A.Z in gene expression may only be uncovered after exposure to cellular stress. To explore this possibility, we generated mRNA transcript profiles for wild-type, htz1Δ, swr1Δ, and htz1Δswr1Δ mutants before and after exposure to hydroxyurea (HU), which induces DNA replication stress. Our data showed that H2A.Z played a more prominent role in gene activation than repression during HU exposure, and its incorporation was important for proper upregulation of several HU-induced genes. We also observed that apo-SWR1-C contributed to gene expression defects in the htz1Δ mutant, particularly for genes involved in phosphate homeostasis regulation. Furthermore, mapping H2A.Z incorporation before and after treatment with HU revealed that decreases in H2A.Z enrichment at transcription start sites was correlated with, but generally not required for, the upregulation of genes during HU exposure. Together this study characterized the regulatory effects of H2A.Z incorporation during the transcriptional response to HU.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011566"},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014553","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":"Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.","authors":"Federica Mosti, Mariah L Hoye, Carla F Escobar-Tomlienovich, Debra L Silver","doi":"10.1371/journal.pgen.1011555","DOIUrl":"10.1371/journal.pgen.1011555","url":null,"abstract":"<p><p>De novo mutations in the RNA binding protein DDX3X cause neurodevelopmental disorders including DDX3X syndrome and autism spectrum disorder. Amongst ~200 mutations identified to date, half are missense. While DDX3X loss of function is known to impair neural cell fate, how the landscape of missense mutations impacts neurodevelopment is almost entirely unknown. Here, we integrate transcriptomics, proteomics, and live imaging to demonstrate clinically diverse DDX3X missense mutations perturb neural development via distinct cellular and molecular mechanisms. Using mouse primary neural progenitors, we investigate four recurrently mutated DDX3X missense variants, spanning clinically severe (2) to mild (2). While clinically severe mutations impair neurogenesis, mild mutations have only a modest impact on cell fate. Moreover, expression of severe mutations leads to profound neuronal death. Using a proximity labeling screen in neural progenitors, we discover DDX3X missense variants have unique protein interactors. We observe notable overlap amongst severe mutations, suggesting common mechanisms underlying altered cell fate and survival. Transcriptomic analysis and subsequent cellular investigation highlights new pathways associated with DDX3X missense variants, including upregulated DNA Damage Response. Notably, clinically severe mutations exhibit excessive DNA damage in neurons, associated with increased cytoplasmic DNA:RNA hybrids and formation of stress granules. These findings highlight aberrant RNA metabolism and DNA damage in DDX3X-mediated neuronal cell death. In sum our findings reveal new mechanisms by which clinically distinct DDX3X missense mutations differentially impair neurodevelopment.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011555"},"PeriodicalIF":4.0,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014675","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":"Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.","authors":"Ying Zhang, Lihong He, Justin Gundelach, Anjie Ge, Helena Edlund, Stefan Norlin, Richard J Bram","doi":"10.1371/journal.pgen.1011547","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011547","url":null,"abstract":"<p><p>Motor neuron diseases, such as amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy, involve loss of muscle control resulting from death of motor neurons. Although the exact pathogenesis of these syndromes remains elusive, many are caused by genetically inherited mutations. Thus, it is valuable to identify additional genes that can impact motor neuron survival and function. In this report, we describe mice that express globally reduced levels of calcium-modulating cyclophilin ligand (CAML) protein. CAML is an essential component in the transmembrane domain recognition complex (TRC) pathway, responsible for inserting C-terminal tail anchored (TA) proteins into the endoplasmic reticulum membrane. The primary phenotype observed in these mice was rapid development of hind limb weakness and paralysis. Spinal cord sections revealed a loss of motor neuron cell bodies. Targeting CAML loss specifically to neurons using SLICK-H-Cre or synapsin-Cre transgenic mice yielded similar phenotypes, indicating that CAML plays a cell autonomous role in this process. We found that intracellular trafficking was perturbed in cells depleted of CAML, with aberrant release of procathepsin D and defective retention of CD222 within the trans-Golgi network, as well as reduced levels and mislocalization of syntaxin 5 (Stx5). Dysfunctional lysosomes and abnormal protein glycosylation were also revealed in CAML deficient cells, further indicating a defect in Golgi trafficking. In addition, we observed an identical phenotype in mice lacking ASNA1 in neurons, suggesting that CAML's role in sustaining muscle function is related to its involvement in the TRC pathway. Together, these findings implicate motor neuron survival as a key role for the TA protein insertion machinery in mice, which may shed light on the pathogenesis of neuromuscular disease in humans.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011547"},"PeriodicalIF":4.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11741622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056105","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":"Short- and long-range roles of UNC-6/Netrin in dorsal-ventral axon guidance in vivo in Caenorhabditis elegans.","authors":"Kelsey M Hooper, Vedant D Jain, Celeste J Gormly, Brian J Sanderson, Erik A Lundquist","doi":"10.1371/journal.pgen.1011526","DOIUrl":"10.1371/journal.pgen.1011526","url":null,"abstract":"<p><p>Recent studies in vertebrates and Caenorhabditis elegans have reshaped models of how the axon guidance cue UNC-6/Netrin functions in dorsal-ventral axon guidance, which was traditionally thought to form a ventral-to-dorsal concentration gradient that was actively sensed by growing axons. In the vertebrate spinal cord, floorplate Netrin1 was shown to be largely dispensable for ventral commissural growth. Rather, short range interactions with Netrin1 on the ventricular zone radial glial stem cells was shown to guide ventral commissural axon growth. In C. elegans, analysis of dorsally-migrating growth cones during outgrowth has shown that growth cone polarity of filopodial extension is separable from the extent of growth cone protrusion. Growth cones are first polarized by UNC-6/Netrin, and subsequent regulation of protrusion by UNC-6/Netrin is based on this earlier-established polarity (the Polarity/Protrusion model). In both cases, short-range or even haptotactic mechanisms are invoked: in vertebrate spinal cord, interactions of growth cones with radial glia expressing Netrin-1; and in C. elegans, a potential close-range interaction that polarizes the growth cone. To explore potential short-range and long-range functions of UNC-6/Netrin, a potentially membrane-anchored transmembrane UNC-6 (UNC-6(TM)) was generated by genome editing. unc-6(tm) was hypomorphic for dorsal VD/DD axon pathfinding, indicating that it retained some unc-6 function. Polarity of VD growth cone filopodial protrusion was initially established in unc-6(tm), but was lost as the growth cones migrated away from the unc-6(tm) source in the ventral nerve cord. In contrast, ventral guidance of the AVM and PVM axons was equally severe in unc-6(tm) and unc-6(null). Together, these results suggest that unc-6(tm) retains short-range functions but lacks long-range functions due to reduced secreted UNC-6. Ectopic unc-6(+) expression from non-ventral sources did not dramatically perturb dorsal VD growth cone polarity or axon outgrowth, suggesting that ectopic UNC-6 cannot redirect polarity once it is established in the VD/DD neurons. This is not what would be expected of a growth cone dynamically reading a gradient of UNC-6, but is consistent with the Polarity/protrusion model of growth cone guidance away from UNC-6/Netrin.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011526"},"PeriodicalIF":4.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11760026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014682","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":"Investigative genetic genealogy practices warranting policy attention: Results of a modified policy Delphi.","authors":"Christi J Guerrini, Louiza Kalokairinou, Jill O Robinson, Whitney Bash Brooks, Stephanie M Fullerton, Sara Huston, Jacklyn Dahlquist, Diana Madden, Norah Crossnohere, Nicola Campoamor, John F P Bridges, Amy L McGuire","doi":"10.1371/journal.pgen.1011520","DOIUrl":"10.1371/journal.pgen.1011520","url":null,"abstract":"<p><p>A technique known as investigative genetic genealogy (IGG) was first introduced to criminal investigations in 2018, and it has since been used by U.S. law enforcement to help identify hundreds of criminal perpetrators and unidentified human remains. As expertise in IGG grows, policymakers have shown interest in regulating it. To help inform these efforts and to promote coherence in IGG governance as it expands, we recruited experts representing a spectrum of IGG-relevant professions and perspectives to identify and prioritize IGG practices for policy attention and to develop policy options for addressing them. In two rounds of a modified policy Delphi, 31 participants prioritized nine IGG practices for policy attention. These top priority practices relate to: consent and notification; case eligibility and criteria; data management, privacy, and security; and governance and accountability. Participants expressed a range of opinions, some strongly held, and did not reach complete consensus with respect to any of the practices. However, convergence was strongest with respect to law enforcement participation in direct-to-consumer genetic genealogy databases against terms of service, which a large majority opposed and almost half evaluated as top priority for policy attention. Participants also voiced strong and consistent concern about management of data and samples collected and generated during IGG and the governance of private laboratories involved in IGG. Our study demonstrates the feasibility and value of engaging with diverse experts over an extended period on a pressing matter of public policy and provides a needed empirical foundation for IGG policymaking.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011520"},"PeriodicalIF":4.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014654","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":"Evolutionary lineage-specific genomic imprinting at the ZNF791 locus.","authors":"Jinsoo Ahn, In-Sul Hwang, Mi-Ryung Park, Milca Rosa-Velazquez, In-Cheol Cho, Alejandro E Relling, Seongsoo Hwang, Kichoon Lee","doi":"10.1371/journal.pgen.1011532","DOIUrl":"https://doi.org/10.1371/journal.pgen.1011532","url":null,"abstract":"<p><p>Genomic imprinting is an epigenetic process that results in parent-of-origin effects on mammalian development and growth. Research on genomic imprinting in domesticated animals has lagged due to a primary focus on orthologs of mouse and human imprinted genes. This emphasis has limited the discovery of imprinted genes specific to livestock. To identify genomic imprinting in pigs, we generated parthenogenetic porcine embryos alongside biparental normal embryos, and then performed whole-genome bisulfite sequencing and RNA sequencing on these samples. In our analyses, we discovered a maternally methylated differentially methylated region within the orthologous ZNF791 locus in pigs. Additionally, we identified both a major imprinted isoform of the ZNF791-like gene and an unannotated antisense transcript that has not been previously annotated. Importantly, our comparative analyses of the orthologous ZNF791 gene in various eutherian mammals, including humans, non-human primates, rodents, artiodactyls, and dogs, revealed that this gene is subjected to genomic imprinting exclusively in domesticated animals, thereby highlighting lineage-specific imprinting. Furthermore, we explored the potential mechanisms behind the establishment of maternal DNA methylation imprints in porcine and bovine oocytes, supporting the notion that integration of transposable elements, active transcription, and histone modification may collectively contribute to the methylation of embedded intragenic CpG island promoters. Our findings convey fundamental insights into molecular and evolutionary aspects of livestock species-specific genomic imprinting and provide critical agricultural implications.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011532"},"PeriodicalIF":4.0,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014661","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":"IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta.","authors":"Marjo K Hytönen, Julius Rönkkö, Sruthi Hundi, Tarja S Jokinen, Emilia Suonto, Eeva Teräväinen, Jonas Donner, Rita La Rovere, Geert Bultynck, Emil Ylikallio, Henna Tyynismaa, Hannes Lohi","doi":"10.1371/journal.pgen.1011328","DOIUrl":"10.1371/journal.pgen.1011328","url":null,"abstract":"<p><p>Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor's dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.</p>","PeriodicalId":49007,"journal":{"name":"PLoS Genetics","volume":"21 1","pages":"e1011328"},"PeriodicalIF":4.0,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11761660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980391","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}