Human molecular genetics最新文献

{"title":"Correction to: Distinct mutations in the autoimmune regulator gene differentially affect transcriptional and functional properties of medullary thymic epithelial cells.","authors":"","doi":"10.1093/hmg/ddag017","DOIUrl":"https://doi.org/10.1093/hmg/ddag017","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432622","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":"Correlations between phenotype and gene region-specific episignatures in Rubinstein-Taybi syndrome and Menke-Hennekam syndrome.","authors":"Yanan Tang, Xiantao Ye, Yongkun Zhan, Kaichuang Zhang, Wenjuan Qiu, WenQing Yang, Xuefan Gu, Yongguo Yu, Bing Xiao, Yu Sun","doi":"10.1093/hmg/ddag006","DOIUrl":"10.1093/hmg/ddag006","url":null,"abstract":"<p><p>Rubinstein-Taybi syndrome (RSTS) and Menke-Hennekam syndrome (MKHK) are two rare Mendelian disorders presented with variable degrees of intellectual disability and different facial dysmorphism. They are caused by loss-of-function (LOF) variants or missense/inframe deletion variants in the exon 30 and 31 of the CREBBP gene respectively. This study aimed to refine the phenotype and provide characterization of genome-wide DNA methylation (DNAm) in RSTS and MKHK. We integrated and analyzed clinical data of 151 patients with RSTS and 36 patients with MKHK from this study and literatures. Meanwhile, genome-wide DNAm analysis were carried out on 51 blood samples (RSTS n = 9, MKHK n = 8, control n = 33), and 21 human induced pluripotent cell (hiPSC) samples (RSTS n = 5, MKHK n = 4, control n = 12). Phenotype analysis showed that patients with RSTS variants downstream the last 50 nt of the penultimate exon had atypical facial malformation and severer medical problems compared to the classical RSTS caused by LOF CREBBP variants. Individuals with MKHK variants in intrinsically disordered region (IDR) showed resemblant features. Meanwhile, DNAm analysis identified two specific blood DNA methylation patterns (episignatures): RSTS and MKHK_IDR compared to matched normal controls. Samples with MKHK variants outside the IDR did not obey the MKHK_IDR episignature. By interrogating DNAm in hiPSCs of patients with RSTS and MKHK, we observed differentially methylated genes play a role in embryonic development and organogenesis. In conclusion, our results suggest that phenotypic features and DNA methylation episignatures may differ for each genomic region.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316751","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":"Updated compendium of genes and variants associated with congenital hypogonadotropic hypogonadism: systematic review, classification pipeline, and network analysis.","authors":"Franco G Brunello, Sebastián Castro, Jonathan Zaiat, Gabriela Sansó, Agustín Izquierdo, Mariela Urrutia, Rodolfo A Rey, Marcelo Martí, Romina P Grinspon, Mariana L Tellechea","doi":"10.1093/hmg/ddag007","DOIUrl":"10.1093/hmg/ddag007","url":null,"abstract":"<p><p>To advance the understanding of Congenital Hypogonadotropic Hypogonadism (CHH), we aimed to refine the catalog of causal genes and variants. We systematically collected variants reported in the literature and created CHH_vd, a curated database. In parallel, we developed CHH_vip, a custom-built computational pipeline for variant annotation and classification, which integrates data from CHH_vd and external sources. Gene network and term enrichment analyses were applied to generate disease-specific gene panels. Our systematic review retrieved 352 scientific studies, documenting 1937 patients carrying a total of 2603 variants, of which 1518 were unique, distributed across 143 genes. All variants were incorporated into CHH_vd (publicly available) and reclassified using CHH_vip according to ACMG/AMP guidelines and ClinGen SVI working group recommendations. Changes in classifications of clinical relevance [from/to Pathogenic, Likely Pathogenic, or High_VUS (Variant of Uncertain Significance with High Probability of Pathogenicity)] were identified for 238 variants when comparing with InterVar, a bioinformatics tool for clinical interpretation of genetic variants. The genes GNRHR, ANOS1, PLXNA1, and SEMA7A were particularly implicated in pathogenicity reassignment, having a comparatively high number of variants downgraded (to more benign). Through CHH_vd, we provide an updated view of the genes impacted by genetic variation in CHH, highlighting marked genetic heterogeneity. The implementation of curated gene panels, combined with CHH_vip, a reproducible platform for compiling and interpreting variation data, may optimize the filtering and classification processes, thereby reducing diagnostic turnaround time.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316774","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":"Cardioprotective SNPs in SLC28A3 and lncRNA SLC28A3-AS1 result in transcriptional changes and alternative splicing to reduce doxorubicin cytotoxicity.","authors":"Shipra Agrawal, Monoj K Das, Tejinder Kaur, Sithumini M W Lokupathirage, Christian Reilly, Mahika Yarram, Rajgopal Govindarajan","doi":"10.1093/hmg/ddag002","DOIUrl":"10.1093/hmg/ddag002","url":null,"abstract":"<p><p>Cardiotoxicity is a therapeutic challenge for anthracycline-based treatments for solid tumors and leukemia. Genome-wide association studies have revealed that single nucleotide polymorphisms in the SLC28A3 locus (encoding Concentrative Nucleoside Transporter 3, CNT3) are significantly associated with reduced doxorubicin-induced cardiotoxicity. However, the mechanistic understanding of the functional effects of these genomic variants is lacking. We designed studies focused on clinically associated SNPs within SLC28A3 using minigenes, site-directed mutagenesis, splicing assays, modulation of SLC28A3 and its antisense long noncoding RNA (lncRNA, AS1), and doxorubicin transport and cytotoxicity measurements to gain more insight. We demonstrated that the cardioprotective synonymous SNP rs7853758 in the Ex14 coding region of SLC28A3 and the variant rs11140490 in Ex1 of its antisense lncRNA (SLC28A3-AS1) have functional consequences in regulating CNT3 transcript and protein expression using alterations in RNA levels and alternative splicing. Additionally, the deep intronic region of Int13, which harbors the SNP rs7030019, is critical for the splicing of CNT3 precursor mRNA at Ex13-14. Furthermore, we identified alternatively spliced variants of the AS1 lncRNA that differentially regulate CNT3 gene expression, doxorubicin transport, and cytotoxicity. Together, these findings suggest that antisense and splicing mechanisms may be exploited to modulate CNT3 function to reduce doxorubicin cytotoxicity, enabling the development of predictive biomarkers and chemotherapeutic management of anthracycline toxicities.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984851","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":"ercc6 deficient zebrafish exhibit UV and metronidazole sensitivity, increased oxygen consumption, and impaired hair cell mechanoelectrical transduction which can be restored by the superoxide dismutase mimetic MnTBAP.","authors":"Gabriel A Hernandez Herrera, Joseph A Dugdale, Jasmine G Wallace, Ryan P Cotter, Alyssa M Jolliffe, Karl J Clark, Lisa A Schimmenti","doi":"10.1093/hmg/ddaf203","DOIUrl":"10.1093/hmg/ddaf203","url":null,"abstract":"<p><p>Cockayne Syndrome is an ultra-rare premature aging condition associated with UV sensitivity, neurocognitive decline, retinopathy, metronidazole-induced lethality, and sensorineural hearing loss. In 70% of affected patients, bi-allelic pathogenic variants in ERCC6 are identified. Although the role of ERCC6 in DNA damage repair has been studied, little is known about the mechanism for defective ERCC6 function in clinical findings, particularly hearing loss. To identify the mechanism of disease caused by pathogenic variants in ERCC6, we developed a zebrafish (Danio rerio) ercc6 loss of function model. We assessed survival after UV and metronidazole exposure, measured basal respiration rates, and evaluated mechanoelectrical transduction function and counts of lateral line hair cells. We found that UV exposure significantly reduces ercc6-/- larval viability. Metronidazole treatment results in complete lethality; wildtype controls show nearly complete survival. ercc6-/- embryos have significantly increased oxygen consumption, suggesting abnormal mitochondrial function. Phalloidin staining of lateral line hair cells with and without UV treatment shows no difference in hair cell counts per neuromast between treatment groups. Mechanoelectrical transduction function after UV exposure, measured by FM1-43 uptake, is reduced. Metronidazole lethality is reduced, oxygen consumption rates are restored, and mechanoelectrical transduction function is preserved by treatment with Mn(III)tetrakis(4-benzoic acid)porphyrin Chloride (MnTBAP), a superoxide dismutase mimetic. We propose that defective mitochondrial function and increased reactive oxygen species levels provide a mechanism for hair cell dysfunction in this model of Cockayne Syndrome. These results provide a foundation for further experiments to explore disease mechanisms and treatment modalities for this premature aging condition.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959285","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-omics investigation of thyroid development and dysfunction in down syndrome.","authors":"Peter Lauffer, Nitash Zwaveling-Soonawala, Andrew Y F Li Yim, Liselot van der Laan, Shama van Zelderen-Bhola, Andrea M Venema, Adri N Mul, Marianna Bugiani, Esther Siteur-van Rijnstra, Quinn D Gunst, Maurice J B van den Hoff, Bernadette S de Bakker, Anita Boelen, Peter Henneman, A S Paul van Trotsenburg","doi":"10.1093/hmg/ddag005","DOIUrl":"10.1093/hmg/ddag005","url":null,"abstract":"<p><strong>Background: </strong>Down syndrome (DS), caused by trisomy of chromosome 21, is associated with a high prevalence of congenital non-autoimmune thyroid dysfunction, typically characterized by an elevated serum thyroid stimulating hormone (TSH) concentration. Early-life observational studies and fetal cordocentesis data, consistently reporting elevated TSH levels, suggest a developmental origin. However, the underlying pathophysiological mechanism remains unclear. This study aimed to investigate the molecular and developmental features underlying thyroid dysfunction in DS.</p><p><strong>Methods: </strong>Thyroid tissue of fetuses with DS (n = 4) and fetuses without a genetic/developmental abnormality (n = 5) were analyzed using histology, bulk RNA sequencing (RNA-seq), and DNA methylation (DNAm) profiling.</p><p><strong>Results: </strong>Histological analysis revealed underdevelopment of DS fetal thyroid tissue, with smaller follicles and greater heterogeneity. RNA-seq identified 1035 differentially expressed genes (DEGs) distributed across the genome. Notably, three thyroid-relevant genes, FOXE1, IYD, and DIO2, were significantly downregulated in DS tissue. Gene set enrichment analysis (GSEA) showed widespread disruption of cellular processes. DNAm analysis identified 266 differentially methylated regions (DMRs), several of which overlapped with loci previously implicated in DS. Integration of expression and DNAm data revealed 20 significant integrative methylation-expression analysis associations, indicating cis-regulatory DNAm effects on gene expression.</p><p><strong>Conclusions: </strong>These findings suggest that congenital thyroid dysfunction in DS represents a DS-specific form of thyroid dysfunction, characterized by impaired thyroid development and altered expression and regulation of genes involved in thyroid function and general cellular processes. The genome-wide molecular changes observed likely result from gene dosage effects and systemic (epi)genomic disturbances caused by trisomy 21.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13036834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147270808","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":"SUPT16H-associated neurodevelopmental disorder and neurocristopathy: genetic and phenotypic spectrum.","authors":"Eunhye Lee, Seungmin Sim, Hee-Jung Choi, Eugene Y Liang, Carolyn Le, Roya Bina, Ryan Cohen, Elizabeth George, Soo Yeon Kim, Gifty Bhat, Erin Falsey, Richard Sidlow, Kristin Clinard, Shay Ben-Shachar, Eleina England, Beatriz Menendez, Isabella Herman, Shelly Nielsen, Jaya Punetha, Priya Bhola, J Austin Hamm, Megan A Keeney, Nike Sitzman, Sara Berger, Lakshmi Mehta, Alison J Conn, Lilian Downie, Myla Ashfaq, Hope Northrup, Ange-Line Bruel, Sylvie Odent, Justin O Szot, Noelia Nunez Martinez, Sunju Park, Julie Refkin, Jean-Marc Good, Fabienne Maurer, Cédric Le Caignec, David J Coman, Erin Anderson, Linda J Richards, Ryan J Dean, Caleb Yang, Chulwon Choi, Byung Joon Hwang, Jin Sook Lee, William B Dobyns, Murim Choi, Elliott H Sherr, Jong-Hee Chae, Yun Kee, Emanuela Argilli","doi":"10.1093/hmg/ddag003","DOIUrl":"10.1093/hmg/ddag003","url":null,"abstract":"<p><p>SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes such as developmental delay, craniofacial anomalies, and hypotonia. Structural and functional analyses of selected SUPT16H variants demonstrated differential rescue of developmental defects in supt16h-deficient embryos, indicating variant-specific LOF effects in vivo. The presence of non-neural manifestations, including facial and ear anomalies, suggested a role for SUPT16H in neural crest development. Consistently, supt16h loss impaired neural crest cell migration and differentiation and triggered p53-dependent apoptosis in the central nervous system (CNS) and neural crest-derived pharyngeal arches. Notably, supt16h deficiency impaired oligodendrocyte specification in the CNS and perturbed differentiation of neural crest-derived Schwann cells in the peripheral nervous system, providing a plausible basis for hypotonia. These findings uncover a previously unrecognized role of SUPT16H in neural crest development, linking chromatin regulation to neural crest-derived lineage specification and differentiation, thereby defining SUPT16H deficiency as a neurocristopathy that broadens the clinical and mechanistic landscape of SUPT16H-associated disorders.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146010211","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":"Individuals with reported and novel KDM5C variants present with seizures, a feature recapitulated in a Drosophila model.","authors":"Bethany K Terry, Amira Mahoney, Brian I Lee, Julie Secombe","doi":"10.1093/hmg/ddag001","DOIUrl":"10.1093/hmg/ddag001","url":null,"abstract":"<p><p>Variants that disrupt the function of the chromatin regulator KDM5C cause a rare neurodevelopmental disorder (KDM5C-NDD) characterized by intellectual disability, seizures, and a broad range of systemic features. To better understand this disorder, more detailed and standardized information is required regarding the association between these genetic variants and cognitive and behavioral traits. Utilizing data obtained by the RARE-X KDM5C Data Collection Program, we analyzed survey and genetic data from 31 newly reported individuals. In addition to the expected neurodevelopmental challenges, participants frequently reported growth abnormalities, vision and digestive issues, behavioral concerns, and seizures in nearly half of the cases. Meta-analyses of this data and previously published cases reaffirmed that seizures are a frequent feature in both hemizygous males and heterozygous females with KDM5C variants, with over a third of individuals reporting at least one seizure. Based on the prevalence of seizures in the RARE-X and published datasets, we sought to develop robust quantitative assays of KDM5-associated seizure behavior using the model organism Drosophila. Reducing the expression of its single Kdm5 gene in neurons, but not glia, led to spontaneous and stimulus-induced seizures, underscoring a cell-intrinsic requirement for KDM5 in maintaining neuronal stability. Together, these human and fly studies highlight KDM5C as a critical regulator of nervous system function, demonstrating how patient-driven data collection and scalable model systems can be effectively integrated. This work expands our understanding of KDM5C-NDD and lays the groundwork for future therapeutic discoveries.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12989173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984920","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":"Functional characterisation of obesity-associated MRAP2 variants on MC4R and GHSR signalling.","authors":"Alejandra V Rodríguez Rondón, Karina Prins, Femke Volker, Eline E P L van der Walle, Cornelis J de Groot, Erica L T van der Akker, Elisabeth F C van Rossum, Mieke M van Haelst, Patric J D Delhanty, Jenny A Visser","doi":"10.1093/hmg/ddag010","DOIUrl":"10.1093/hmg/ddag010","url":null,"abstract":"<p><p>Melanocortin-2 receptor accessory protein-2 (MRAP2) modulates the activity of hypothalamic melanocortin-4 (MC4R) and growth hormone-secretagogue (GHSR) receptors, which suppress and promote appetite, respectively. We investigate whether obesity-associated variants of MRAP2 alter their ability to modulate MC4R and GHSR signalling as a possible mechanistic link to the development of obesity. Functional effects of five obesity-associated MRAP2 variants were analysed in HEK293 cells by co-expressing wild-type or variant MRAP2 with MC4R or GHSR. Endpoints included cell-surface and total expression, and ligand-induced second-messenger responses, β-arrestin-2 recruitment, and alternative G-protein activation. MRAP2 decreased basal MC4R cell-surface expression while GHSR cell-surface expression was not affected. In MC4R/MRAP2 expressing cells, maximal α-MSH-induced cAMP and β-arrestin-2 recruitment responses were increased. Similarly, ghrelin-induced Ca2+-mobilization in GHSR/MRAP2 expressing cells was increased, but β-arrestin-2 recruitment was suppressed. MRAP2 did not bias G-protein activation by either receptor, although previous reports show MRAP2 biases MC4R signalling towards Gαq/11. The variants did not significantly affect the ability of MRAP2 to modulate MC4R and GHSR signalling. Our results indicate that MRAP2 potentiates the ligand responsiveness of MC4R and GHSR, but has differential effects on β-arrestin-2 recruitment. The MRAP2 variants had no significant effects on the signalling endpoints tested. This suggests that, despite their association with obesity, the variants may be functionally benign, or that the absence of effects reflects limitations inherent to our cellular model. In addition, since MRAP2 can modulate multiple receptors and differentially modulate their signalling, we cannot rule out their influence on body weight regulation via other mechanisms.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 5","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13017093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316836","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":"Retinol dehydrogenase 10-mediated retinoic acid signaling regulates the neural crest cell microenvironment during enteric nervous system formation.","authors":"Naomi E Butler Tjaden, Stephen R Shannon, Thoa H K Truong, Christopher W Seidel, Melissa Childers, Kazushi Aoto, Lisa L Sandell, Paul A Trainor","doi":"10.1093/hmg/ddaf197","DOIUrl":"10.1093/hmg/ddaf197","url":null,"abstract":"<p><p>The enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, it's important to identify new genes, modifiers, and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, retinoic acid (RA), and is therefore a central regulator of vitamin A metabolism and RA synthesis during embryogenesis. We discovered that retinol dehydrogenase 10 (Rdh10) loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate in Rdh10 mutant embryos but fail to invade the foregut. Rdh10 is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5 and E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of the Ret-Gdnf-Gfrα1 gene signaling network in Rdh10 mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively, this restricts NCC entry into the gut, demonstrating that Rdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145933112","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}