Disease Models & Mechanisms最新文献_第8页

Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome. 鸡胚胎颅面研究证实了与罗宾诺综合征相关的人类 FZD2 变体的致病性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-07-05 DOI: 10.1242/dmm.050584

Shruti S Tophkhane, Katherine Fu, Esther M Verheyen, Joy M Richman

{"title":"Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome.","authors":"Shruti S Tophkhane, Katherine Fu, Esther M Verheyen, Joy M Richman","doi":"10.1242/dmm.050584","DOIUrl":"10.1242/dmm.050584","url":null,"abstract":"Robinow syndrome is a rare disease caused by variants of seven WNT pathway genes. Craniofacial features include widening of the nasal bridge and jaw hypoplasia. We used the chicken embryo to test whether two missense human FZD2 variants (1301G>T, p.Gly434Val; 425C>T, p.Pro142Lys) were sufficient to change frontonasal mass development. In vivo, the overexpression of retroviruses with wild-type or variant human FZD2 inhibited upper beak ossification. In primary cultures, wild-type and variant human FZD2 significantly inhibited chondrogenesis, with the 425C>T variant significantly decreasing activity of a SOX9 luciferase reporter compared to that for the wild type or 1301G>T. Both variants also increased nuclear shuttling of β-catenin (CTNNB1) and increased the expression of TWIST1, which are inhibitory to chondrogenesis. In canonical WNT luciferase assays using frontonasal mass cells, the variants had dominant-negative effects on wild-type FZD2. In non-canonical assays, the 425C>T variant failed to activate the reporter above control levels and was unresponsive to exogenous WNT5A. This is the first single amino acid change to selectively alter ligand binding in a FZD receptor. Therefore, FZD2 missense variants are pathogenic and could lead to the altered craniofacial morphogenesis seen in Robinow syndrome.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141533945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis. Smad4 限制损伤诱发的胆道增殖和癌变。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-02-28 DOI: 10.1242/dmm.050358

William B Alexander, Wenjia Wang, Margaret A Hill, Michael R O'Dell, Luis I Ruffolo, Bing Guo, Katherine M Jackson, Nicholas Ullman, Scott C Friedland, Matthew N McCall, Ankit Patel, Nathania Figueroa-Guilliani, Mary Georger, Brian A Belt, Christa L Whitney-Miller, David C Linehan, Patrick J Murphy, Aram F Hezel

{"title":"Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.","authors":"William B Alexander, Wenjia Wang, Margaret A Hill, Michael R O'Dell, Luis I Ruffolo, Bing Guo, Katherine M Jackson, Nicholas Ullman, Scott C Friedland, Matthew N McCall, Ankit Patel, Nathania Figueroa-Guilliani, Mary Georger, Brian A Belt, Christa L Whitney-Miller, David C Linehan, Patrick J Murphy, Aram F Hezel","doi":"10.1242/dmm.050358","DOIUrl":"10.1242/dmm.050358","url":null,"abstract":"Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 6","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10924230/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139982628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of genetic suppressors for a BSCL2 lipodystrophy pathogenic variant in Caenorhabditis elegans. 鉴定草履虫 BSCL2 脂肪营养不良致病变体的基因抑制因子

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-04-16 DOI: 10.1242/dmm.050524

Xiaofei Bai, Harold E Smith, Andy Golden

{"title":"Identification of genetic suppressors for a BSCL2 lipodystrophy pathogenic variant in Caenorhabditis elegans.","authors":"Xiaofei Bai, Harold E Smith, Andy Golden","doi":"10.1242/dmm.050524","DOIUrl":"10.1242/dmm.050524","url":null,"abstract":"Seipin (BSCL2), a conserved endoplasmic reticulum protein, plays a critical role in lipid droplet (LD) biogenesis and in regulating LD morphology, pathogenic variants of which are associated with Berardinelli-Seip congenital generalized lipodystrophy type 2 (BSCL2). To model BSCL2 disease, we generated an orthologous BSCL2 variant, seip-1(A185P), in Caenorhabditis elegans. In this study, we conducted an unbiased chemical mutagenesis screen to identify genetic suppressors that restore embryonic viability in the seip-1(A185P) mutant background. A total of five suppressor lines were isolated and recovered from the screen. The defective phenotypes of seip-1(A185P), including embryonic lethality and impaired eggshell formation, were significantly suppressed in each suppressor line. Two of the five suppressor lines also alleviated the enlarged LDs in the oocytes. We then mapped a suppressor candidate gene, lmbr-1, which is an ortholog of human limb development membrane protein 1 (LMBR1). The CRISPR/Cas9 edited lmbr-1 suppressor alleles, lmbr-1(S647F) and lmbr-1(P314L), both significantly suppressed embryonic lethality and defective eggshell formation in the seip-1(A185P) background. The newly identified suppressor lines offer valuable insights into potential genetic interactors and pathways that may regulate seipin in the lipodystrophy model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11051982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140058908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice. 一种小分子 TrkB 配体可改善雌性 Rett 综合征小鼠的树突棘表型和非典型行为。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-05-24 DOI: 10.1242/dmm.050612

Destynie Medeiros, Karen Ayala-Baylon, Hailey Egido-Betancourt, Eric Miller, Christopher Chapleau, Holly Robinson, Mary L Phillips, Tao Yang, Frank M Longo, Wei Li, Lucas Pozzo-Miller

{"title":"A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.","authors":"Destynie Medeiros, Karen Ayala-Baylon, Hailey Egido-Betancourt, Eric Miller, Christopher Chapleau, Holly Robinson, Mary L Phillips, Tao Yang, Frank M Longo, Wei Li, Lucas Pozzo-Miller","doi":"10.1242/dmm.050612","DOIUrl":"10.1242/dmm.050612","url":null,"abstract":"Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11139040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141087308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Translating multiscale research in rare disease. 转化罕见病的多尺度研究。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-07-10 DOI: 10.1242/dmm.052009

Kirsty M Hooper, Monica J Justice, Monkol Lek, Karen J Liu, Katherine A Rauen

引用次数: 0

Fbrsl1 is required for heart development in Xenopus laevis and de novo variants in FBRSL1 can cause human heart defects. Fbrsl1 是爪蟾心脏发育所必需的，FBRSL1 的新生变体可导致人类心脏缺陷。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-05-14 DOI: 10.1242/dmm.050507

Hanna Berger, Sarah Gerstner, Marc-Frederik Horstmann, Silke Pauli, Annette Borchers

{"title":"Fbrsl1 is required for heart development in Xenopus laevis and de novo variants in FBRSL1 can cause human heart defects.","authors":"Hanna Berger, Sarah Gerstner, Marc-Frederik Horstmann, Silke Pauli, Annette Borchers","doi":"10.1242/dmm.050507","DOIUrl":"10.1242/dmm.050507","url":null,"abstract":"De novo truncating variants in fibrosin-like 1 (FBRSL1), a member of the AUTS2 gene family, cause a disability syndrome, including organ malformations such as heart defects. Here, we use Xenopus laevis to investigate whether Fbrsl1 plays a role in heart development. Xenopus laevis fbrsl1 is expressed in tissues relevant for heart development, and morpholino-mediated knockdown of Fbrsl1 results in severely hypoplastic hearts. Our data suggest that Fbrsl1 is required for the development of the first heart field, which contributes to the ventricle and the atria, but not for the second heart field, which gives rise to the outflow tract. The morphant heart phenotype could be rescued using a human N-terminal FBRSL1 isoform that contains an alternative exon, but lacks the AUTS2 domain. N-terminal isoforms carrying patient variants failed to rescue. Interestingly, a long human FBRSL1 isoform, harboring the AUTS2 domain, also did not rescue the morphant heart defects. Thus, our data suggest that different FBRSL1 isoforms may have distinct functions and that only the short N-terminal isoform, appears to be critical for heart development.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11128277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Founder mutations and rare disease in the Arab world. 阿拉伯世界的基因突变和罕见疾病。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-06-26 DOI: 10.1242/dmm.050715

Dana Marafi

引用次数: 0

Piecing together the mosaic of rare skin diseases: an interview with Veronica Kinsler. 拼凑罕见皮肤病的马赛克：采访 Veronica Kinsler。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-01-18 DOI: 10.1242/dmm.050636

Veronica A Kinsler

引用次数: 0

Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases. 与人类遗传疾病相关的 ATP8A2 和其他 P4-ATP 酶变体的功能分析和 In-silico 分析。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-04-24 DOI: 10.1242/dmm.050546

Eli Matsell, Jens Peter Andersen, Robert S Molday

{"title":"Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.","authors":"Eli Matsell, Jens Peter Andersen, Robert S Molday","doi":"10.1242/dmm.050546","DOIUrl":"10.1242/dmm.050546","url":null,"abstract":"P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We determined the expression, localization and ATPase activity of four variants of ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, impaired intellectual development and disequilibrium syndrome 4 (CAMRQ4). Two variants, G447R and A772P, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells. In contrast, the E459Q variant in a flexible loop displayed wild-type expression levels, Golgi-endosome localization and ATPase activity. The R1147W variant expressed at 50% of wild-type levels but showed normal localization and activity. These results indicate that the G447R and A772P mutations cause CAMRQ4 through protein misfolding. The E459Q mutation is unlikely to be causative, whereas the R1147W may display a milder disease phenotype. Using various programs that predict protein stability, we show that there is a good correlation between the experimental expression of the variants and in silico stability assessments, suggesting that such analysis is useful in identifying protein misfolding disease-associated variants.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Igniting an autoinflammatory disease community: an interview with Ian Stedman. 点燃自身炎症性疾病社区：采访伊恩-斯特德曼（Ian Stedman）。

IF 4.3 3区医学

Disease Models & Mechanisms Pub Date : 2024-06-01 Epub Date: 2024-01-17 DOI: 10.1242/dmm.050642

Ian Stedman

引用次数: 0