Human molecular genetics最新文献_第5页

Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases. 从序列到表达的方法识别 P53 和 cMYC 驱动型疾病中的病因非编码 DNA 变异。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-19 DOI: 10.1093/hmg/ddae109

Katherine Kin, Shounak Bhogale, Lisha Zhu, Derrick Thomas, Jessica Bertol, W Jim Zheng, Saurabh Sinha, Walid D Fakhouri

{"title":"Sequence-to-expression approach to identify etiological non-coding DNA variations in P53 and cMYC-driven diseases.","authors":"Katherine Kin, Shounak Bhogale, Lisha Zhu, Derrick Thomas, Jessica Bertol, W Jim Zheng, Saurabh Sinha, Walid D Fakhouri","doi":"10.1093/hmg/ddae109","DOIUrl":"10.1093/hmg/ddae109","url":null,"abstract":"Disease risk prediction based on genomic sequence and transcriptional profile can improve disease screening and prevention. Despite identifying many disease-associated DNA variants, distinguishing deleterious non-coding DNA variations remains poor for most common diseases. In this study, we designed in vitro experiments to uncover the significance of occupancy and competitive binding between P53 and cMYC on common target genes. Analyzing publicly available ChIP-seq data for P53 and cMYC in embryonic stem cells showed that ~344-366 regions are co-occupied, and on average, two cis-overlapping motifs (CisOMs) per region were identified, suggesting that co-occupancy is evolutionarily conserved. Using U2OS and Raji cells untreated and treated with doxorubicin to increase P53 protein level while potentially reducing cMYC level, ChIP-seq analysis illustrated that around 16 to 922 genomic regions were co-occupied by P53 and cMYC, and substitutions of cMYC signals by P53 were detected post doxorubicin treatment. Around 187 expressed genes near co-occupied regions were altered at mRNA level according to RNA-seq data analysis. We utilized a computational motif-matching approach to illustrate that changes in predicted P53 binding affinity in CisOMs of co-occupied elements significantly correlate with alterations in reporter gene expression. We performed a similar analysis using SNPs mapped in CisOMs for P53 and cMYC from ChIP-seq data, and expression of target genes from GTEx portal. We found significant correlation between change in cMYC-motif binding affinity in CisOMs and altered expression. Our study brings us closer to developing a generally applicable approach to filter etiological non-coding variations associated with common diseases.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626614","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}

引用次数: 0

Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels 在 MECP2 重复综合征人 iPSC 衍生神经元中模拟反义寡核苷酸疗法，揭示与 MeCP2 水平相关的基因表达程序

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae135

Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi

{"title":"Modeling antisense oligonucleotide therapy in MECP2 duplication syndrome human iPSC-derived neurons reveals gene expression programs responsive to MeCP2 levels","authors":"Sameer S Bajikar, Yehezkel Sztainberg, Alexander J Trostle, Harini P Tirumala, Ying-Wooi Wan, Caroline L Harrop, Jesse D Bengtsson, Claudia M B Carvalho, Davut Pehlivan, Bernhard Suter, Jeffrey L Neul, Zhandong Liu, Paymaan Jafar-Nejad, Frank Rigo, Huda Y Zoghbi","doi":"10.1093/hmg/ddae135","DOIUrl":"https://doi.org/10.1093/hmg/ddae135","url":null,"abstract":"Genomic copy-number variations (CNVs) that can cause neurodevelopmental disorders often encompass many genes, which complicates our understanding of how individual genes within a CNV contribute to pathology. MECP2 duplication syndrome (MDS or MRXSL in OMIM; OMIM#300260) is one such CNV disorder caused by duplications spanning methyl CpG-binding protein 2 (MECP2) and other genes on Xq28. Using an antisense oligonucleotide (ASO) to normalize MECP2 dosage is sufficient to rescue abnormal neurological phenotypes in mouse models overexpressing MECP2 alone, implicating the importance of increased MECP2 dosage within CNVs of Xq28. However, because MDS CNVs span MECP2 and additional genes, we generated human neurons from multiple MDS patient-derived induced pluripotent cells (iPSCs) to evaluate the benefit of using an ASO against MECP2 in a MDS human neuronal context. Importantly, we identified a signature of genes that is partially and qualitatively modulated upon ASO treatment, pinpointed genes sensitive to MeCP2 function, and altered in a model of Rett syndrome, a neurological disorder caused by loss of MeCP2 function. Furthermore, the signature contained genes that are aberrantly altered in unaffected control human neurons upon MeCP2 depletion, revealing gene expression programs qualitatively sensitive to MeCP2 levels in human neurons. Lastly, ASO treatment led to a partial rescue of abnormal neuronal morphology in MDS neurons. All together, these data demonstrate that ASOs targeting MECP2 benefit human MDS neurons. Moreover, our study establishes a paradigm by which to evaluate the contribution of individual genes within a CNV to pathogenesis and to assess their potential as a therapeutic target.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255572","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}

引用次数: 0

Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease TTN 单倍变体导致骨骼肌疾病的病理机制

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae136

Jochen Gohlke, Johan Lindqvist, Zaynab Hourani, Sarah Heintzman, Paola Tonino, Bakri Elsheikh, Ana Morales, Matteo Vatta, Arthur Burghes, Henk Granzier, Jennifer Roggenbuck

{"title":"Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease","authors":"Jochen Gohlke, Johan Lindqvist, Zaynab Hourani, Sarah Heintzman, Paola Tonino, Bakri Elsheikh, Ana Morales, Matteo Vatta, Arthur Burghes, Henk Granzier, Jennifer Roggenbuck","doi":"10.1093/hmg/ddae136","DOIUrl":"https://doi.org/10.1093/hmg/ddae136","url":null,"abstract":"Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255571","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}

引用次数: 0

Deciphering single-cell gene expression variability and its role in drug response 解密单细胞基因表达变异及其在药物反应中的作用

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-15 DOI: 10.1093/hmg/ddae138

Sizhe Liu, Liang Chen

引用次数: 0

Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions 运动神经元病患者纹状体中的亨廷蛋白小包涵体，具有低渗透性和中等 HTT 基因扩增性

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-14 DOI: 10.1093/hmg/ddae137

Anna-Karin Roos, Erica Stenvall, Emmy Skelton Kockum, Kornelia Åman Grönlund, Helena Alstermark, Anna Wuolikainen, Peter M Andersen, Angelica Nordin, Karin M E Forsberg

{"title":"Small striatal huntingtin inclusions in patients with motor neuron disease with reduced penetrance and intermediate HTT gene expansions","authors":"Anna-Karin Roos, Erica Stenvall, Emmy Skelton Kockum, Kornelia Åman Grönlund, Helena Alstermark, Anna Wuolikainen, Peter M Andersen, Angelica Nordin, Karin M E Forsberg","doi":"10.1093/hmg/ddae137","DOIUrl":"https://doi.org/10.1093/hmg/ddae137","url":null,"abstract":"Short tandem repeat expansions in the human genome are overrepresented in a variety of neurological disorders. It was recently shown that huntingtin (HTT) repeat expansions with full penetrance, i.e. 40 or more CAG repeats, which normally cause Huntington’s disease (HD), are overrepresented in patients with amyotrophic lateral sclerosis (ALS). Whether patients carrying HTT repeat expansions with reduced penetrance, (36–39 CAG repeats), or alleles with intermediate penetrance, (27–35 CAG repeats), have an increased risk of ALS has not yet been investigated. Here, we examined the role of HTT repeat expansions in a motor neuron disease (MND) cohort, searched for expanded HTT alleles, and investigated correlations with phenotype and neuropathology. MND patients harboring C9ORF72 hexanucleotide repeat expansions (HREs) were included, to investigate whether HTT repeat expansions were more common in this group. We found a high prevalence of intermediate (range 5.63%–6.61%) and reduced penetrance (range 0.57%–0.66%) HTT gene expansions in this cohort compared to other populations of European ancestry, but no differences between the MND cohort and the control cohort were observed, regardless of C9ORF72HRE status. Upon autopsy of three patients with intermediate or reduced penetrance HTT alleles, huntingtin inclusions were observed in the caudate nucleus and frontal lobe, but no significant somatic mosaicism was detected in different parts of the nervous system. Thus, we demonstrate, for the first time, huntingtin inclusions in individuals with MND and intermediate and reduced penetrance HTT repeat expansions but more clinicopathological investigations are needed to further understand the impact of HTT gene expansion-related pleiotropy.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255598","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}

引用次数: 0

Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial syndrome with a variant in ACTB 肌动蛋白动力学受损是巴莱泽-温特脑颌面综合征口唇裂的基础，该综合征伴有 ACTB 变异

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-14 DOI: 10.1093/hmg/ddae133

Takayuki Tsujimoto, Yushi Ou, Makoto Suzuki, Yuka Murata, Toshihiro Inubushi, Miho Nagata, Yasuki Ishihara, Ayumi Yonei, Yohei Miyashita, Yoshihiro Asano, Norio Sakai, Yasushi Sakata, Hajime Ogino, Takashi Yamashiro, Hiroshi Kurosaka

{"title":"Compromised actin dynamics underlie the orofacial cleft in Baraitser-Winter Cerebrofrontofacial syndrome with a variant in ACTB","authors":"Takayuki Tsujimoto, Yushi Ou, Makoto Suzuki, Yuka Murata, Toshihiro Inubushi, Miho Nagata, Yasuki Ishihara, Ayumi Yonei, Yohei Miyashita, Yoshihiro Asano, Norio Sakai, Yasushi Sakata, Hajime Ogino, Takashi Yamashiro, Hiroshi Kurosaka","doi":"10.1093/hmg/ddae133","DOIUrl":"https://doi.org/10.1093/hmg/ddae133","url":null,"abstract":"Craniofacial anomalies encompassing the orofacial cleft are associated with &gt; 30% of systemic congenital malformations. Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF) is a rare genetic disorder attributed to variants in the actin beta (ACTB) or actin gamma genes that are correlated with a range of craniofacial abnormalities, including cleft lip and/or palate. The underlying pathological mechanism of BWCFF remains elusive, and it is necessary to investigate the etiology of orofacial clefts in patients with BWCFF. In this study, we identified a missense variant (c.1043C &gt; T: p.S348L) in the ACTB gene of a patient with BWCFF and concomitant cleft lip and palate. Furthermore, we performed functional assessments of this variant using various disease models such as the MDCK cell line and Xenopus laevis. These models revealed a compromised capacity of mutated ACTB to localize to the epithelial junction, consequently affecting the behavior of epithelial cells. Additionally, we discovered that the mutated ACTB exhibited an impaired ability to bind PROFILIN1, a critical factor in actin polymerization. This defective ability may contribute to the molecular etiology of aberrant epithelial cell adhesion and migration, resulting in orofacial cleft formation in BWCFF.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255599","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}

引用次数: 0

Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer α9-烟碱受体单核苷酸多态性诱导乳腺癌致癌特性和分子机制研究

IF 3.5 2区生物学

Human molecular genetics Pub Date : 2024-09-05 DOI: 10.1093/hmg/ddae132

You-Cheng Liao, Lu-Hai Wang, Mien-Chie Hung, Tzu-Chun Cheng, Ying-Chi Lin, Jungshan Chang, Shih-Hsin Tu, Chih-Hsiung Wu, Yun Yen, Yi-Chen Hsieh, Li-Ching Chen, Yuan-Soon Ho

{"title":"Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer","authors":"You-Cheng Liao, Lu-Hai Wang, Mien-Chie Hung, Tzu-Chun Cheng, Ying-Chi Lin, Jungshan Chang, Shih-Hsin Tu, Chih-Hsiung Wu, Yun Yen, Yi-Chen Hsieh, Li-Ching Chen, Yuan-Soon Ho","doi":"10.1093/hmg/ddae132","DOIUrl":"https://doi.org/10.1093/hmg/ddae132","url":null,"abstract":"α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A &gt; G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene–environment interactions carefully while developing effective breast cancer prevention and treatment strategies.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184595","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}

引用次数: 0

Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases. 在酵母中研究与线粒体疾病相关的线粒体氨基酰-tRNA合成酶 WARS2、NARS2 和 RARS2 基因的新型变体。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-03 DOI: 10.1093/hmg/ddae104

Sonia Figuccia, Rossella Izzo, Andrea Legati, Alessia Nasca, Paola Goffrini, Daniele Ghezzi, Camilla Ceccatelli Berti

{"title":"Investigation in yeast of novel variants in mitochondrial aminoacyl-tRNA synthetases WARS2, NARS2, and RARS2 genes associated with mitochondrial diseases.","authors":"Sonia Figuccia, Rossella Izzo, Andrea Legati, Alessia Nasca, Paola Goffrini, Daniele Ghezzi, Camilla Ceccatelli Berti","doi":"10.1093/hmg/ddae104","DOIUrl":"10.1093/hmg/ddae104","url":null,"abstract":"Aminoacyl-transfer RiboNucleic Acid synthetases (ARSs) are essential enzymes that catalyze the attachment of each amino acid to their cognate tRNAs. Mitochondrial ARSs (mtARSs), which ensure protein synthesis within the mitochondria, are encoded by nuclear genes and imported into the organelle after translation in the cytosol. The extensive use of next generation sequencing (NGS) has resulted in an increasing number of variants in mtARS genes being identified and associated with mitochondrial diseases. The similarities between yeast and human mitochondrial translation machineries make yeast a good model to quickly and efficiently evaluate the effect of variants in mtARS genes. Genetic screening of patients with a clinical suspicion of mitochondrial disorders through a customized gene panel of known disease-genes, including all genes encoding mtARSs, led to the identification of missense variants in WARS2, NARS2 and RARS2. Most of them were classified as Variant of Uncertain Significance. We exploited yeast models to assess the functional consequences of the variants found in these genes encoding mitochondrial tryptophanyl-tRNA, asparaginyl-tRNA, and arginyl-tRNA synthetases, respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate, Cox2 steady-state level and mitochondrial protein synthesis were analyzed in yeast strains deleted in MSW1, SLM5, and MSR1 (the yeast orthologues of WARS2, NARS2 and RARS2, respectively), and expressing the wild type or the mutant alleles. Pathogenicity was confirmed for most variants, leading to their reclassification as Likely Pathogenic. Moreover, the beneficial effects observed after asparagine and arginine supplementation in the growth medium suggest them as a potential therapeutic approach.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125580","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}

引用次数: 0

The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway. 先天性 Shoc2 变体的表达会诱导 AKT 依赖性串联激活 ERK1/2 通路。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-03 DOI: 10.1093/hmg/ddae100

Patricia G Wilson, Lina Abdelmoti, Tianyan Gao, Emilia Galperin

{"title":"The expression of congenital Shoc2 variants induces AKT-dependent crosstalk activation of the ERK1/2 pathway.","authors":"Patricia G Wilson, Lina Abdelmoti, Tianyan Gao, Emilia Galperin","doi":"10.1093/hmg/ddae100","DOIUrl":"10.1093/hmg/ddae100","url":null,"abstract":"The Shoc2 scaffold protein is crucial in transmitting signals within the Epidermal Growth Factor Receptor (EGFR)-mediated Extracellular signal-Regulated Kinase (ERK1/2) pathway. While the significance of Shoc2 in this pathway is well-established, the precise mechanisms through which Shoc2 governs signal transmission remain to be fully elucidated. Hereditary variants in Shoc2 are responsible for Noonan Syndrome with Loose anagen Hair (NSLH). However, due to the absence of known enzymatic activity in Shoc2, directly assessing how these variants affect its function is challenging. ERK1/2 phosphorylation is used as a primary parameter of Shoc2 function, but the impact of Shoc2 mutants on the pathway activation is unclear. This study investigates how the NSLH-associated Shoc2 variants influence EGFR signals in the context of the ERK1/2 and AKT downstream signaling pathways. We show that when the ERK1/2 pathway is a primary signaling pathway activated downstream of EGFR, Shoc2 variants cannot upregulate ERK1/2 phosphorylation to the level of the WT Shoc2. Yet, when the AKT and ERK1/2 pathways were activated, in cells expressing Shoc2 variants, ERK1/2 phosphorylation was higher than in cells expressing WT Shoc2. In cells expressing the Shoc2 NSLH mutants, we found that the AKT signaling pathway triggers the PAK activation, followed by phosphorylation of Raf-1/MEK1/2 and activation of the ERK1/2 signaling axis. Hence, our studies reveal a previously unrecognized feedback regulation downstream of the EGFR and provide additional evidence for the role of Shoc2 as a \"gatekeeper\" in controlling the selection of downstream effectors within the EGFR signaling network.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373329/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141330779","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}

引用次数: 0

The maternal protein NLRP5 stabilizes UHRF1 in the cytoplasm: implication for the pathogenesis of multilocus imprinting disturbance. 母体蛋白NLRP5在细胞质中稳定UHRF1：与多焦点印记紊乱的发病机制有关。

IF 3.1 2区生物学

Human molecular genetics Pub Date : 2024-09-03 DOI: 10.1093/hmg/ddae096

Motoko Unoki, Shuhei Uemura, Akihiro Fujimoto, Hiroyuki Sasaki

{"title":"The maternal protein NLRP5 stabilizes UHRF1 in the cytoplasm: implication for the pathogenesis of multilocus imprinting disturbance.","authors":"Motoko Unoki, Shuhei Uemura, Akihiro Fujimoto, Hiroyuki Sasaki","doi":"10.1093/hmg/ddae096","DOIUrl":"10.1093/hmg/ddae096","url":null,"abstract":"We have recently discovered that the so-called subcortical maternal complex (SCMC) proteins composing of cytoplasmic lattices are destabilized in Uhrf1 knockout murine fully grown oocytes (FGOs). Here we report that human UHRF1 interacts with human NLRP5 and OOEP, which are core components of the SCMC. Moreover, NLRP5 and OOEP interact with DPPA3, which is an essential factor for exporting UHRF1 from the nucleus to the cytoplasm in oocytes. We identify that NLRP5, not OOEP, stabilizes UHRF1 protein in the cytoplasm utilizing specifically engineered cell lines mimicking UHRF1 status in oocytes and preimplantation embryos. Further, UHRF1 is destabilized both in the cytoplasm and nucleus of Nlrp5 knockout murine FGOs. Since pathogenic variants of the SCMC components frequently cause multilocus imprinting disturbance and UHRF1 is essential for maintaining CpG methylation of imprinting control regions during preimplantation development, our results suggest possible pathogenesis behind the disease, which has been a long-standing mystery.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310563","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}

引用次数: 0