Human molecular genetics最新文献

{"title":"Motor pool selectivity of neuromuscular degeneration in type I spinal muscular atrophy is conserved between human and mouse.","authors":"Justin C Lee, Wendy K Chung, David J Pisapia, Christopher E Henderson","doi":"10.1093/hmg/ddae190","DOIUrl":"10.1093/hmg/ddae190","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein. Even though SMN is ubiquitously expressed, the disease selectively affects motor neurons, leading to progressive muscle weakness. Even among motor neurons, certain motor units appear more clinically resistant to SMA. To quantitatively survey selective resistance, we studied extensive neuromuscular autopsies of Type I SMA patients and age-matched controls. We found highly divergent degrees of degeneration of neighboring motor units, even within individual cranial nerves or a single anatomical area such as the neck. Examination of a Type I SMA patient maintained on life support for 17 years found that most muscles were atrophied, but the diaphragm was strikingly preserved. Nevertheless, some resistant human muscles with preserved morphology displayed nearly complete conversion to slow Type I myofibers. Remarkably, a similar pattern of selective resistance was observed in the SMNΔ7 mouse model. Overall, differential motor unit vulnerability in human Type I SMA suggests the existence of potent, motor unit-specific disease modifiers. Mechanisms that confer selective resistance to SMA may represent therapeutic targets independent of the SMN protein, particularly in patients with neuromuscular weakness refractory to current treatments.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"347-367"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846572","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":"Dissecting the shared genetic architecture between nonalcoholic fatty liver disease and type 2 diabetes.","authors":"Zhenqiu Liu, Xiaochen Chen, Huangbo Yuan, Li Jin, Tiejun Zhang, Xingdong Chen","doi":"10.1093/hmg/ddae184","DOIUrl":"10.1093/hmg/ddae184","url":null,"abstract":"<p><p>Observational studies have reported a bidirectional correlation between nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D), but the shared genetic basis between the two conditions remains unclear. Using genome-wide association study (GWAS) summary data from European-ancestry populations, we examined the cross-trait genetic correlation and identified genomic overlaps and shared risk loci. We employed a latent causal variable model and Mendelian randomization (MR) analysis to infer causal relationships. Colocalization analysis and conditional/conjunctional false discovery rate (condFDR/conjFDR) were used to identify genomic overlaps and shared risk loci. Two-step MR analysis was utilized to identify potential mediators. We observed a strong positive genomic correlation between NAFLD and T2D (rg = 0.652, P = 5.67 × 10-6) and identified tissue-specific transcriptomic correlations in the pancreas, liver, skeletal muscle, subcutaneous adipose, and blood. Genetic enrichment was observed in NAFLD conditional on associations with T2D and vice versa, indicating significant polygenic overlaps. We found robust evidence for the causal effect of NAFLD on T2D, particularly insulin-related T2D, rather than vice versa. Colocalization analysis identified shared genomic regions between NAFLD and T2D, including GCKR, FTO, MAU2-TM6SF2, and PNPLA3-SAMM50. High-density lipoprotein cholesterol and insulin were partly mediated the association between NAFLD and T2D. These findings unveil a close genetic link between NAFLD and T2D, shedding light on the biological mechanisms connecting NAFLD progression to T2D.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"338-346"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846505","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":"Identification of hub genes and biological pathways related to central post-stroke pain in ischemic stroke.","authors":"Fude Liu, Yawen Cheng, Xiangning Han, Ning Zhu, Shiliang Jiang, Jiahao Li, Wenlong Ma, Jia Yu","doi":"10.1093/hmg/ddae178","DOIUrl":"10.1093/hmg/ddae178","url":null,"abstract":"<p><p>This investigation aims to screen ischemic stroke (IS)-related hub genes of central post-stroke pain (CPSP) from public databases and predict their potential roles through bioinformatics analysis to better interpret CPSP in IS. First, based on differential analysis, Venn analysis, and enrichment analyses, we identified 13 differently expressed genes in CPSP (CPSP-DEGs) related to the TNF signaling pathway, Vascular smooth muscle contraction, and IL-17 signaling pathway. Subsequently, through screening and analysis of the PPI network constructed by the Search Tool for the Retrieval of Interacting Genes (STRING) database, we obtained 3 CPSP-related hub genes (CD163, MMP9, and ARG1). They were all highly expressed in the IS group, exhibiting good diagnostic performance, with area under curve (AUC) value > 0.85. The immune-related analysis demonstrated that the infiltration levels of various immune cells in the IS group and the normal group were substantially different. In addition, by utilizing some online websites, we not only predicted some microRNAs (miRNAs) and transcription factors (TFs) that may target hub genes but also mined small molecular drugs that may target differentially expressed genes (DEGs) in IS. In conclusion, this project first investigated the role of CPSP-related genes in IS and identified 3 hub genes. At the same time, we predicted some miRNAs, TFs, and candidate drugs that may target hub genes. Our research uncovered the potential mechanism of CPSP-related genes in IS from multiple perspectives. Furthermore, it also laid a research foundation for the future study of the mechanisms of IS disease.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"304-312"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806867","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 miR-129-5p in regulating γ-globin expression and erythropoiesis in β-thalassemia.","authors":"Jingmin Li, Meihuan Chen, Wantong Zhao, Aixiang Lv, Siyang Lin, Yanping Zheng, Meiying Cai, Na Lin, Liangpu Xu, Hailong Huang","doi":"10.1093/hmg/ddae180","DOIUrl":"10.1093/hmg/ddae180","url":null,"abstract":"<p><p>The regulation of γ-globin expression is crucial due to its beneficial effects on diseases like β-thalassemia and sickle cell disease. B-cell lymphoma/leukemia 11A (BCL11A) is a significant suppressor of γ-globin, and microRNAs (miRNAs) targeting BCL11A have been shown to alleviate this suppression. In our previous high-throughput sequencing, we identified an 11.32-fold increase in miR-129-5p expression in β-thalassemia patients. However, the regulatory mechanisms of miR-129-5p in the context of erythroid differentiation remain to be elucidated. Our study aimed to elucidate the role of miR-129-5p in γ-globin regulation and erythropoiesis. We measured miR-129-5p levels in peripheral blood from β-thalassemia major and intermedia patients. Fluorescence in situ hybridization, dual-luciferase reporter assays, miRNA pull down assays and western blot analyses were conducted to examine the effects of miR-129-5p on γ-globin expression and BCL11A repression. Cell proliferation, apoptosis, and erythroid differentiation were assessed using cell counting kit-8, Wright-Giemsa, and benzidine staining, and flow cytometry assays. The expression levels of miR-129-5p were significantly elevated in β-thalassemia patients and positively correlated with γ-globin synthesis while negatively correlating with liver damage. miR-129- 5p enhanced γ-globin gene expression in K562 and HUDEP-2 cells by effectively repressing BCL11A. Overexpression of miR-129-5p inhibited cell proliferation, induced cell cycle arrest at the G1/G0 phase, promoted apoptosis and stimulated erythroid differentiation and maturation. Conversely, inhibition of miR-129-5p produced opposite cellular effects. miR-129-5p acts as a positive regulator of erythroid differentiation and γ-globin synthesis. It offers a promising miRNA target for activating the γ-globin gene and reducing ineffective erythropoiesis in β-thalassemia patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"291-303"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806899","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":"Identification of ZNF850 as a novel CTG repeat expansion-related gene in myotonic dystrophy type 1 patient-derived iPSCs.","authors":"Masayoshi Kamon, Shuji Wakatsuki, Masayuki Nakamori, Masanori P Takahashi, Madoka Mori-Yoshimura, Hirofumi Komaki, Toshiyuki Araki","doi":"10.1093/hmg/ddae186","DOIUrl":"10.1093/hmg/ddae186","url":null,"abstract":"<p><p>Myotonic dystrophy type 1 (DM1) is a dominantly inherited multi-system disease caused by expanded CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Similar to other repeat disorders, the expanded trinucleotide repeat is unstable and demonstrates a tendency to increase repeat size with age in affected tissues. DNA mismatch repair system is implicated in somatic instability. It has been demonstrated that DM1 patient-derived induced pluripotent stem cells (DM1-iPSCs) show repeat instability, in which involvement of mismatch repair proteins has been suggested. Here we identified ZNF850 as a novel CTG repeat expansion-related molecule in DM1-iPSCs. ZNF850 was downregulated in a DM1-iPSC clone whose CTG repeat is exceptionally stable. We found that RNAi-mediated ZNF850 downregulation in DM1-iPSCs significantly reduced the repeat expansion and resulting instability. In adult skeletal muscle tissue of DM1 patients, ZNF850 expression levels were positively correlated with the repeat size. Furthermore, we found that ZNF850 protein can bind to the expanded CTG repeat sequence, and is located in proximity to MutSβ components. These results suggest that ZNF850 might play a role in repeat instability in DM1 by recruiting MutSβ to the repeat sequence.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"327-337"},"PeriodicalIF":3.1,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828382","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":"Recruitment of chromatin remodelers by XIST B-repeat region is variably dependent on HNRNPK.","authors":"Maria Jose Navarro-Cobos, Carolyn J Brown","doi":"10.1093/hmg/ddae173","DOIUrl":"10.1093/hmg/ddae173","url":null,"abstract":"<p><p>X-chromosome inactivation is triggered by the long non-coding RNA XIST, whose structure is characterized by tandem repeats that modularly recruit different proteins and chromatin remodelers. Previously, we reported that the addition of the mouse PID region to a transgene with human repeat regions A, F and E (miniXIST; 5.1 kb) enabled binding of HNRNPK and also enabled the induction of silencing and recruitment of H3K27me3, UbH2A and H4K20me1, but only partially. As the 680 bp PID region enabled so many features of inactivation, we hypothesized that augmenting the PID with more mouse or human sequences rich in CCC motifs would allow us to design a short transgene which was as effective as Full XIST. Three new transgenes using the A, F and E human domains as a backbone were tested for ability to induce silencing and heterochromatic mark recruitment. The all human-derived BhB-BhB transgene (4.9 kb) was as good as our previous miniXIST, suggesting that these domains are the human equivalent of the mouse PID region. A PID-PID transgene (5.8 kb) was not statistically different from Full XIST and could be potentially used for chromosome therapy. Adding BhB to PID (BhB-PID, 5.4 kb) had an intermediate efficacy compared to the other two transgenes, suggesting that the most important component for silencing and heterochromatic mark recruitment is the number of CCC motifs, not the species of origin. Finally, we created a heterozygous HNRNPK deletion and observed a disproportionate impact on HNRNPK and UbH2A recruitment to XIST, reflecting complex roles for the PID and HNRNPK in X-chromosome inactivation.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"229-238"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715976","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":"Genetic architecture of RNA editing, splicing and gene expression in schizophrenia.","authors":"Mudra Choudhury, Ryo Yamamoto, Xinshu Xiao","doi":"10.1093/hmg/ddae172","DOIUrl":"10.1093/hmg/ddae172","url":null,"abstract":"<p><p>Genome wide association studies (GWAS) have been conducted over the past decades to investigate the underlying genetic origin of neuropsychiatric diseases, such as schizophrenia (SCZ). While these studies demonstrated the significance of disease-phenotype associations, there is a pressing need to fully characterize the functional relevance of disease-associated genetic variants. Functional genetic loci can affect transcriptional and post-transcriptional phenotypes that may contribute to disease pathology. Here, we investigate the associations between genetic variation and RNA editing, splicing, and overall gene expression through identification of quantitative trait loci (QTL) in the CommonMind Consortium SCZ cohort. We find that editing QTL (edQTL), splicing QTL (sQTL) and expression QTL (eQTL) possess both unique and common gene targets, which are involved in many disease-relevant pathways, including brain function and immune response. We identified two QTL that fall into all three QTL categories (seedQTL), one of which, rs146498205, targets the lincRNA gene, RP11-156P1.3. In addition, we observe that the RNA binding protein AKAP1, with known roles in neuronal regulation and mitochondrial function, had enriched binding sites among edQTL, including the seedQTL, rs146498205. We conduct colocalization with various brain disorders and find that all QTL have top colocalizations with SCZ and related neuropsychiatric diseases. Furthermore, we identify QTL within biologically relevant GWAS loci, such as in ELA2, an important tRNA processing gene associated with SCZ risk. This work presents the investigation of multiple QTL types in parallel and demonstrates how they target both distinct and overlapping SCZ-relevant genes and pathways.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"277-290"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828376","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":"The role of complement factor I rare genetic variants in age related macular degeneration in Finland.","authors":"Anneliza Andreadi, Thomas M Hallam, Vicky Brocklebank, Scott J Sharp, Patrick R Walsh, Tom Southerington, Marco Hautalahti, David H Steel, Andrew J Lotery, Claire L Harris, Kevin J Marchbank, David Kavanagh, Amy V Jones","doi":"10.1093/hmg/ddae165","DOIUrl":"10.1093/hmg/ddae165","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The alternative pathway (AP) of complement has been linked to the pathogenesis of AMD. In particular, rare variants (RVs) in the complement factor I (CFI) gene encoding the Factor I (FI) protein confer increased AMD risk. The prevalence of CFI RVs are well characterised in European AMD, however little is known about other populations. The Finnish population underwent genetic restriction events which have skewed allele frequencies in unexpected ways. A series of novel or enriched CFI RVs were identified in individuals with dry AMD from the Finnish Biobank Cooperative (FINBB), but the relationship between these genotypes and contribution to disease was unclear. Understanding how RVs impact the ability of FI to regulate the complement system is important to inform mechanistic understanding for how different genotypes contribute to disease development. To explore this a series of in vitro assays were used to functionally characterise the protein products of 3 CFI RVs enriched in FINBB dry AMD, where no prior data were available. The G547R variant resulted in almost complete loss of both classical pathway and AP regulatory potential. The c.982 g>a variant encoding G328R FI perturbed an exon splice enhancer site which resulted in exon skipping and a premature stop codon in vitro and low levels of FI in vivo. Despite detailed analysis no defect in levels or function was demonstrated in T107A. Functional characterization of all Finnish CFI RVs in the cohort allowed us to demonstrate that in Finnish dry AMD, collectively the type 1 CFI RVs (associated with FI haploinsufficiency) were significantly enriched with odds ratio (ORs) of 72.6 (95% confidence interval; CI 16.92 to 382.1). Meanwhile, type 2 CFI RVs (associated with FI dysfunction) collectively conferred a significant OR of 4.97 (95% CI 1.522 to 15.74), and non-impaired or normal CFI RV collectively conferred an of OR 3.19 (95% CI 2.410 to 4.191) although this was driven primarily by G261D. Overall, this study for the first time determined the ORs and functional effect for all CFI RVs within a Geographic Atrophy (GA) cohort, enabling calculations of combined risk scores that underline the risk conferred by type 1 and 2 CFI RVs in GA/AMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"218-228"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142710031","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":"The genetic architecture of hip shape and its role in the development of hip osteoarthritis and fracture.","authors":"Benjamin G Faber, Monika Frysz, Jaiyi Zheng, Huandong Lin, Kaitlyn A Flynn, Raja Ebsim, Fiona R Saunders, Rhona Beynon, Jennifer S Gregory, Richard M Aspden, Nicholas C Harvey, Claudia Lindner, Timothy Cootes, David M Evans, George Davey Smith, Xin Gao, Sijia Wang, John P Kemp, Jonathan H Tobias","doi":"10.1093/hmg/ddae169","DOIUrl":"10.1093/hmg/ddae169","url":null,"abstract":"<p><strong>Objectives: </strong>Hip shape is thought to be an important causal risk factor for hip osteoarthritis and fracture. We aimed to identify genetic determinants of hip shape and use these to assess causal relationships with hip osteoarthritis.</p><p><strong>Methods: </strong>Statistical hip shape modelling was used to derive 10 hip shape modes (HSMs) from DXA images in UK Biobank and Shanghai Changfeng cohorts (ntotal = 43 485). Genome-wide association study meta-analyses were conducted for each HSM. Two-sample Mendelian randomisation (MR) was used to estimate causal effects between HSM and hip osteoarthritis using hip fracture as a positive control.</p><p><strong>Results: </strong>Analysis of the first 10 HSMs identified 203 independent association signals (P < 5 × 10-9). Hip shape SNPs were also associated (P < 2.5 × 10-4) with hip osteoarthritis (n = 26) and hip fracture (n = 4). Fine mapping implicated SMAD3 and PLEC as candidate genes that may be involved in the development of hip shape and hip osteoarthritis. MR analyses suggested there was no causal effect between any HSM and hip osteoarthritis, however there was evidence that HSM2 (more obtuse neck-shaft angle) and HSM4 (wider femoral neck) have a causal effect on hip fracture (ORIVW method 1.27 [95% CI 1.12-1.44], P = 1.79 × 10-4 and ORIVW 0.74 [0.65-0.84], P = 7.60 × 10-6 respectively).</p><p><strong>Conclusions: </strong>We report the largest hip shape GWAS meta-analysis that identifies hundreds of novel loci, some of which are also associated with hip osteoarthritis and hip fracture. MR analyses suggest hip shape may not cause hip osteoarthritis but is implicated in hip fractures. Consequently, interventions targeting hip shape in older adults to prevent hip osteoarthritis may prove ineffective.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"207-217"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686895","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":"Development of a riboflavin-responsive model of riboflavin transporter deficiency in zebrafish.","authors":"Catherine M Choueiri, Jarred Lau, Emily O'Connor, Alicia DiBattista, Brittany Y Wong, Sally Spendiff, Rita Horvath, Izabella Pena, Alexander MacKenzie, Hanns Lochmüller","doi":"10.1093/hmg/ddae171","DOIUrl":"10.1093/hmg/ddae171","url":null,"abstract":"<p><p>Riboflavin transporter deficiency (RTD) is a rare and progressive neurodegenerative disease resulting from the disruption of RFVT2- and RFVT3- mediated riboflavin transport caused by biallelic mutations in SLC52A2 and SLC52A3, respectively. The resulting impaired mitochondrial metabolism leads to sensorimotor neurodegeneration and symptoms including muscle weakness, respiratory difficulty, and sensorineural deafness. Although over 70% of patients with RTD improve following high-dose riboflavin supplementation, remaining patients either stabilise or continue to deteriorate. This may be due to the rapid excretion of central nervous system (CNS) riboflavin by organic anion transporter 3 (OAT-3), highlighting the need for alternative or supplemental RTD treatments. Probenecid is a promising therapeutic candidate for RTD due to its known inhibitory effect on OAT-3. Therefore, this study aimed to generate morpholino-mediated knockdowns of human SLC52A3 ortholog slc52a3 in zebrafish larvae for use in therapeutic screening of riboflavin and probenecid. Knockdown of slc52a3 resulted in an RTD-like phenotype indicative of altered neurodevelopment, hearing loss, and reduced mobility. This RTD-like phenotype overlaps with the phenotype of CRISPR/Cas9-mediated knockout of slc52a3 in zebrafish, is maintained following slc52a3 morpholino + p53 morpholino co-injection, and is rescued following slc52a3 morpholino + human SLC52A3 mRNA co-injection, indicating specificity of the knockdown. Riboflavin treatment alone ameliorates locomotor activity and hearing ability in slc52a3 morphants. Riboflavin and probenecid co-treatment provides an additional small benefit to hearing but not to locomotion. Our findings demonstrate that this model recapitulates both the RTD phenotype and the riboflavin-responsiveness of RTD patients, and possible therapeutic benefit conferred by probenecid warrants further investigation.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"265-276"},"PeriodicalIF":3.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828373","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}