Human molecular genetics最新文献

{"title":"Non-canonical imprinting, manifesting as post-fertilization placenta-specific parent-of-origin dependent methylation, is not conserved in humans.","authors":"Dagne Daskeviciute, Louise Chappell-Maor, Becky Sainty, Philippe Arnaud, Isabel Iglesias-Platas, Carlos Simon, Hiroaki Okae, Takahiro Arima, Rita Vassena, Jon Lartey, David Monk","doi":"10.1093/hmg/ddaf009","DOIUrl":"https://doi.org/10.1093/hmg/ddaf009","url":null,"abstract":"<p><p>Genomic imprinting is the parent-of-origin dependent monoallelic expression of genes often associated with regions of germline-derived DNA methylation that are maintained as differentially methylated regions (gDMRs) in somatic tissues. This form of epigenetic regulation is highly conserved in mammals and is thought to have co-evolved with placentation. Tissue-specific gDMRs have been identified in human placenta, suggesting that species-specific imprinting dependent on unorthodox epigenetic establishment or maintenance may be more widespread than previously anticipated. Non-canonical imprinting, reliant on differential allelic H3K27me3 enrichment, has been reported in mouse and rat pre-implantation embryos, often overlapping long terminal repeat (LTR)-derived promoters. These non-canonical imprints lose parental allele-specific H3K27me3 specificity, subsequently gaining DNA methylation on the same allele in extra-embryonic tissues resulting in placenta-specific, somatically acquired maternal DMRs. To determine if similar non-canonical imprinting is present in the human placenta, we interrogated allelic DNA methylation for a selected number of loci, including (i) the human orthologues of non-canonical imprinted regions in mouse and rat, (ii) promoters of human LTR-derived transcripts, and (iii) CpG islands with intermediate placenta-specific methylation that are unmethylated in gametes and pre-implantation embryos. We failed to identify any non-canonical imprints in the human placenta whole villi samples. Furthermore, the assayed genes were shown to be biallelically expressed in human pre-implantation embryos, indicating they are not imprinted at earlier time points. Together, our work reiterates the continued evolution of placenta-specific imprinting in mammals, which we suggest is linked to epigenetic differences during the maternal-to-embryo transition and species-specific integration of retrotransposable elements.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004502","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":"Functional variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with increased risk of colorectal cancer.","authors":"Anna Prizment, Abby Standafer, Conghui Qu, Kathleen M Beutel, Shuo Wang, Wen-Yi Huang, Annika Lindblom, Rachel Pearlman, Bethany Van Guelpen, Alicja Wolk, Daniel D Buchanan, Robert C Grant, Stephanie L Schmit, Elizabeth A Platz, Corinne E Joshu, David J Couper, Ulrike Peters, Timothy K Starr, Patricia Scott, Nathan Pankratz","doi":"10.1093/hmg/ddaf007","DOIUrl":"https://doi.org/10.1093/hmg/ddaf007","url":null,"abstract":"<p><strong>Background: </strong>Individuals with cystic fibrosis (CF; a recessive disorder) have an increased risk of colorectal cancer (CRC). Evidence suggests individuals with a single CFTR variant may also have increased CRC risk.</p><p><strong>Methods: </strong>Using population-based studies (GECCO, CORECT, CCFR, and ARIC; 53 785 CRC cases and 58 010 controls), we tested for an association between the most common CFTR variant (Phe508del) and CRC risk. For replication, we used whole exome sequencing data from UK Biobank (UKB; 5126 cases and 20 504 controls matched 4:1 based on genetic distance, age, and sex), and extended our analyses to all other heterozygous CFTR variants annotated as CF-causing.</p><p><strong>Results: </strong>In our meta-analysis of GECCO-CORECT-CCFR-ARIC, the odds ratio (OR) for CRC risk associated with Phe508del was 1.11 (P = 0.010). In our UKB replication, the OR for CRC risk associated with Phe508del was 1.28 (P = 0.002). The sequencing data from UKB also revealed an association between the presence of any other single CF-causing variant (excluding Phe508del) and CRC risk (OR = 1.33; P = 0.030). When stratifying CFTR variants by functional class, class I variants (no protein produced) had a stronger association (OR = 1.77; p = 0.002), while class II variants (misfolding and retention of the protein in the endoplasmic reticulum) other than Phe508del (OR = 1.75; p = 0.107) had similar effect size as Phe508del, and variants in classes III-VI had non-significant ORs less than 1.0 and/or were not present in cases.</p><p><strong>Conclusions: </strong>CF-causing heterozygous variants, especially class I variants, are associated with a modest but statistically significant increased CRC risk. More research is needed to explain the biology underlying these associations.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004225","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":"Rare and common genetic variants underlying the risk of Hirschsprung's disease.","authors":"Jun Xiao, Chenzhao Feng, Tianqi Zhu, Xuan Zhang, Xuyong Chen, Zejian Li, Jingyi You, Qiong Wang, Didi Zhuansun, Xinyao Meng, Jing Wang, Lei Xiang, Xiaosi Yu, Bingyan Zhou, Weibing Tang, Jinfa Tou, Yi Wang, Heying Yang, Lei Yu, Yuanmei Liu, Xuewu Jiang, Hongxia Ren, Mei Yu, Qi Chen, Qiang Yin, Xiang Liu, Zhilin Xu, Dianming Wu, Donghai Yu, Xiaojuan Wu, Jixin Yang, Bo Xiong, Feng Chen, Xingjie Hao, Jiexiong Feng","doi":"10.1093/hmg/ddae205","DOIUrl":"https://doi.org/10.1093/hmg/ddae205","url":null,"abstract":"<p><p>Hirschsprung's disease (HSCR) is a congenital enteric neuropathic disorder characterized by high heritability (>80%) and polygenic inheritance (>20 genes). The previous genome-wide association studies (GWAS) identified several common variants associated with HSCR and demonstrated increased predictive performance for HSCR risk in Europeans using a genetic risk score, there remains a notable gap in knowledge regarding Chinese populations. We conducted whole exome sequencing in a HSCR case cohort in Chinese. By using the common controls (505 controls from 1KG EAS and 10 588 controls from ChinaMAP), we conducted GWAS for the common variants in the exome and gene-based association for rare variants. We further validated the associated variants and genes in replicated samples and in vitro and vivo experiments. We identified one novel gene PLK5 by GWAS and suggested 45 novel putative genes based the gene-based test. By using genetic variant at RET and PLK5, we constructed a genetic risk score that could identify the individuals with very high genetic risk for HSCR. Compared with patients with zero or one risk allele from the three variants, the risk for HSCR was 36.61 times higher with six alleles. In addition, we delineated a HSCR risk gene landscape that encompasses 57 genes, which explains 88.5% and 54.5% of HSCR in Chinese and European, respectively. In summary, this study improved the understanding of genetic architecture of HSCR and provided a risk prediction approach for HSCR in the Chinese.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004503","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":"Choroid plexus-targeted viral gene therapy for alpha-mannosidosis, a prototypical neurometabolic lysosomal storage disease.","authors":"Eun-Young Choi, John H Wolfe, Stephen G Kaler","doi":"10.1093/hmg/ddae201","DOIUrl":"https://doi.org/10.1093/hmg/ddae201","url":null,"abstract":"<p><p>The choroid plexuses (CP) are highly vascularized structures that project into the ventricles of the vertebrate brain. The polarized epithelia of the CP produce cerebrospinal fluid by transporting water and ions into the ventricles from the blood and normally secrete a large number of proteins. We assessed the feasibility of selective CP transduction with recombinant adeno-associated virus (rAAV) gene therapy vectors for treatment of lysosomal storage disease (LSD), a broad category of neurometabolic illness associated with significant burdens to affected patients and their families. There are no ideal or complete therapeutic options currently available, especially for the central nervous system manifestations of LSDs. Alpha-mannosidosis (AMD) is an autosomal recessive prototypical LSD caused by deficiency of lysosomal alpha-mannosidase and characterized by cerebellar ataxia, neurocognitive disability, facial and skeletal abnormalities, hearing impairment, and mild immune deficiency. In a murine model of AMD, we compared the biochemical effects of CSF-directed rAAV serotypes 1, 4, 5, 6, and 9. Recombinant AAV1 and rAAV6, two closely related serotypes whose capsid sequences differ by only six amino acids, showed the most robust transduction of CP in mouse brain, consistent with their transduction of CPE in nonhuman primates and cats, as well as in other structures. We found restoration of LAMAN enzyme activity comparable to or higher than AMD heterozygote levels in the brain globally (olfactory bulb, cortex, cerebellum, brainstem). Further IND-generating preclinical experiments will advance rAAV6-LAMAN, which appears to be the most promising choroid plexus-targeting candidate serotype for future clinical translation to treat AMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004627","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":"Regulatory role of miR-128-2-5p in serum exosomes on COL6A2 expression and postmenopausal osteoporosis.","authors":"Liangjie Lu, Lijun Wang, Huihan Wang, Minjie Yang","doi":"10.1093/hmg/ddae147","DOIUrl":"https://doi.org/10.1093/hmg/ddae147","url":null,"abstract":"<p><p>This study investigates the influence of miR-128-2-5p within serum-derived exosomes (Exos) on COL6A2 expression and its implications in postmenopausal osteoporosis (POMP). Utilizing bioinformatics analysis, we identified 1317 differentially expressed genes (DEGs), primarily enriched in the focal adhesion pathway-a critical regulator of osteoblast adhesion. A significant gene, COL6A2, emerged as notably downregulated in POMP, possessing potential as a diagnostic marker. Predictive analysis linked the upstream miRNA miR-128-2-5p, highly enriched in Exos, with the regulation of COL6A2. Experimentally, Exos from POMP patients demonstrated elevated miR-128-2-5p levels, which inhibited COL6A2 expression in vitro, reducing osteoblast adhesion and exacerbating osteoporotic conditions. These findings highlight the pivotal role of exosomal miR-128-2-5p in bone metabolism, suggesting a novel molecular mechanism and a potential therapeutic target in POMP.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004541","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":"Alterations in cardiac function correlate with a disruption in fatty acid metabolism in a mouse model of SMA.","authors":"Nithya N Nair, Rachel A Kline, Imogen Boyd, Meenakshi Anikumar, Adrian Thomson, Douglas J Lamont, Gillian A Gray, Thomas M Wishart, Lyndsay M Murray","doi":"10.1093/hmg/ddaf006","DOIUrl":"https://doi.org/10.1093/hmg/ddaf006","url":null,"abstract":"<p><p>Spinal Muscular Atrophy is an autosomal dominant disease caused by mutations and deletions within the SMN1 gene, with predominantly childhood onset. Although primarily a motor neuron disease, defects in non-neuronal tissues are described in both patients and mouse models. Here, we have undertaken a detailed study of the heart in the Smn2B/- mouse models of SMA, and reveal a thinning of the ventriclar walls as previously described in more severe mouse models of SMA. However most structural changes are resolved by accounting for the smaller body size of the SMA mouse, as was also confirmed in the SMN∆7 model. Echocardiography revealed increased systolic function, which was particularly pronounced in subsets of mice and an increase in global longitudinal strain, collectively indicative of increased cardiac stress in the Smn2B/- mouse model. We have used TMT proteomics to perform a longitudinal study of the proteome of the hearts of Smn2B/- mice and reveal a progressive dysregulation of LXR/RXR signalling which is a regulator of lipid metabolism. We further show consistent perturbations in lipid metabolism in the Smn2B/-, Smn-/-;SMN2;SmnΔ7and SmnΔ7/Δ7;SMN2 mouse models of SMA on the day of birth. This work indicates that although structural changes in the heart can be overstated by failing to account for body size, there are functional defects which could predispose the heart to subsequent failure. We identify a common molecular signature across mouse models pointing to a dysregulation in lipid metabolism, and suggest that manipulation of LXR/RXR signalling offers an opportunity to impact upon these pathways.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983243","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":"The role of CNBP in brain atrophy and its targeting in myotonic dystrophy type 2.","authors":"Katherine Jennings, Diana Lindquist, Ankita Poonia, Benedikt Schoser, Christiane Schneider-Gold, Nikolai A Timchenko, Lubov Timchenko","doi":"10.1093/hmg/ddaf002","DOIUrl":"https://doi.org/10.1093/hmg/ddaf002","url":null,"abstract":"<p><p>Myotonic Dystrophy type 2 (DM2) is a multisystem disease affecting many tissues, including skeletal muscle, heart, and brain. DM2 is caused by unstable expansion of CCTG repeats in an intron 1 of a gene coding for cellular nuclear binding protein (CNBP). The expanded CCTG repeats cause DM2 pathology due to the accumulation of RNA CCUG repeats, which affect RNA processing in patients' cells. We have previously shown that mutant CCUG repeats reduce CNBP protein in DM2 patients. Reducing Cnbp in Cnbp KO mouse model causes late skeletal muscle atrophy. In this study, we examined if the reduction of Cnbp affects the Central Nervous System (CNS). MRI and DTI analyses showed that total brain volume and grey matter are reduced in Cnbp KO mice, while mean, radial and axonal brain diffusivity is increased. The morphological changes in the brains of Cnbp KO mice are accompanied by reduced stereotypic behavior, anxiety and neuromotor defects. These findings suggest that the reduction of CNBP contributes to CNS pathology in DM2. Since CNBP stability is regulated by pAMPK-dependent phosphorylation, we examined protein levels of pAMPK in DM2 cells and found that the active pAMPK is reduced in DM2. Interaction of CNBP with pAMPK and stability of CNBP protein are also decreased in DM2. Our data show that a small molecule AMPK activator A769662 corrects CNBP stability and normalizes CNBP targets in DM2 fibroblasts. Thus, activators of AMPK could potentially be developed as therapeutics to correct CNBP and reduce muscle and brain atrophies in DM2.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978306","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":"UBE2S, downregulated by miR-152-3p, facilitates prostate cancer progression through the PTEN-mediated AKT/mTOR pathway.","authors":"Chunhui Wang, Gang Zhang, Ying Jiang, Guochang Bao, Chunsheng Li","doi":"10.1093/hmg/ddaf004","DOIUrl":"https://doi.org/10.1093/hmg/ddaf004","url":null,"abstract":"<p><strong>Objectives: </strong>In recent years, the incidence and mortality rates of prostate cancer (PCa) have still not been significantly reduced and the mechanisms of tumor onset and progression are still not fully understood. The pathogenic mechanisms and upstream regulation of UBE2S expression in prostate cancer have not been elucidated.</p><p><strong>Methods: </strong>Here, we performed bioinformatic analysis of public databases to reveal the expression of UBE2S in PCa and its association with Gleason score, tumor staging, biochemical recurrence, and survival. Subsequently, the effect of UBE2S on the proliferation and invasive capacity of PCa cells was explored. Next, miR-152-3p was identified to bind to the 3'-UTR of UBE2S mRNA and down-regulated in PCa through luciferase reporter assays. Dual immunofluorescence assay and co-immunoprecipitation assays were performed to verify the regulatory role of UBE2S on PTEN. Finally, the molecular mechanism of UBE2S regulation of PCa progression was further confirmed by rescue experiments and in vivo nude mouse subcutaneous transplantation tumor experiments.</p><p><strong>Results: </strong>UBE2S expression was upregulated in PCa and correlated with patient Gleason score, TNM stage, biochemical recurrence, and disease-free survival. miR-152-3p regulated UBE2S expression in PCa by binding to the UBE2S mRNA 3'-UTR. Mechanistically, UBE2S combines with PTEN and ubiquitinates it, leading to PTEN degradation and ultimately promoting PCa progression via the AKT/mTOR signaling pathway.</p><p><strong>Conclusions: </strong>UBE2S, down-regulated by miR-152-3p, plays an important role in the onset and progression of PCa through the PTEN-mediated Akt/mTOR pathway and may become a new diagnostic marker and therapeutic target for PCa.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978307","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":"Study on the metastatic mechanism of LINC00115 in adenocarcinoma of the Esophagogastric junction.","authors":"Xia Zhao, Haifeng Zhang, Yangyang Liu, Li Li, Haitao Wei","doi":"10.1093/hmg/ddae193","DOIUrl":"https://doi.org/10.1093/hmg/ddae193","url":null,"abstract":"<p><p>Adenocarcinoma of the esophagogastric junction (AEG) is a common and deadly cancer, and an in-depth investigation of its molecular mechanisms of metastasis is crucial for discovering new therapeutic targets. This study explores the role of the long non-coding RNA (lncRNA) LINC00115 in AEG metastasis and its underlying mechanisms. Through the analysis of 108 pairs of AEG cancer tissues and matched adjacent tissues, we found a significant upregulation of LINC00115 in AEG tissues, closely associated with TNM staging and lymph node metastasis. Utilizing cell counting kit-8 (CCK-8) assays, colony formation experiments, wound healing assays, flow cytometry for apoptosis and cell cycle analysis, and Transwell assays, we have confirmed that LINC00115 significantly promotes proliferation, migration, and invasion of AEG cells in vitro. Animal experiments further validate the role of LINC00115 in promoting tumor growth and metastasis in vivo. Additionally, our nuclear-cytoplasmic fractionation experiments and RNA fluorescence in situ hybridization (FISH) reveal that LINC00115, along with its interacting protein KH-Type splicing regulatory protein (KHSRP), predominantly localizes to the cell nucleus. By conducting RNA pull-down assays and mass spectrometry (MS) analysis, we have identified a direct interaction between LINC00115 and KHSRP protein and further determined their binding sites through catRAPID and ENCORI databases. This study provides evidence of LINC00115 as a novel biomarker and potential therapeutic target for AEG and offers a fresh perspective on understanding the molecular mechanisms of AEG metastasis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978305","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":"Obesity-associated MRAP2 variants impair multiple MC4R-mediated signaling pathways.","authors":"Rachael A Wyatt, Aqfan Jamaluddin, Vinesh Mistry, Caitlin Quinn, Caroline M Gorvin","doi":"10.1093/hmg/ddaf005","DOIUrl":"https://doi.org/10.1093/hmg/ddaf005","url":null,"abstract":"<p><p>The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor expressed at hypothalamic neurons that has an important role in appetite suppression and food intake. Mutations in MC4R are the most common cause of monogenic obesity and can affect multiple signaling pathways including Gs-cAMP, Gq, ERK1/2, β-arrestin recruitment, internalization and cell surface expression. The melanocortin-2 receptor accessory protein 2 (MRAP2), is a single-pass transmembrane protein that interacts with and regulates signaling by MC4R. Variants in MRAP2 have also been identified in overweight and obese individuals. However, functional studies that have only measured the effect of MRAP2 variants on MC4R-mediated cAMP signaling have produced inconsistent findings and most do not reduce MC4R function. Here we investigated the effect of twelve of these previously reported MRAP2 variants and showed that all variants that have been identified in overweight or obese individuals impair MC4R function. When expressed at equal concentrations, seven MRAP2 variants impaired MC4R-mediated cAMP signaling, while nine variants impaired IP3 signaling. Four mutations in the MRAP2 C-terminus affected internalization. MRAP2 variants had no effect on total or cell surface expression of either the MRAP2 or MC4R proteins. Structural models predicted that MRAP2 interacts with MC4R transmembrane helices 5 and 6, and mutations in two MRAP2 residues in putative contact sites impaired the ability of MRAP2 to facilitate MC4R signaling. In summary, our studies demonstrate that human MRAP2 variants associated with obesity impair multiple MC4R signaling pathways and that both Gs-cAMP and Gq-IP3 pathways should be assessed to determine variant pathogenicity.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142978304","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}