Human molecular genetics最新文献

{"title":"Utrophin requires α-Syntrophin to maintain neuromuscular junction integrity in mdx mice.","authors":"Alissa Wierenga, Michelle Mendoza, Saad O Malik, Akash Agrawal, Aya Reda, Abigail Maag, Ameen Abou-Rjaily, Chenlang Gao, Mohammed Akaaboune","doi":"10.1093/hmg/ddag060","DOIUrl":"10.1093/hmg/ddag060","url":null,"abstract":"<p><p>Dystrophin links the actin cytoskeleton to the extracellular matrix through the dystrophin-glycoprotein complex (DGC), providing structural stability to muscle fibers. In mdx mice, which lack dystrophin, neuromuscular junctions (NMJs) remain largely structurally and functionally intact despite extensive muscle pathology. Here, using single- and double-mutant mice deficient in dystrophin and α-syntrophin (α-syn), we investigated how utrophin upregulation contributes to NMJ maintenance in dystrophic muscle. During early postnatal development, when dystrophic muscles are transiently resistant to degeneration, the DGC proteins α-dystrobrevin, α-syn, and β-dystroglycan are broadly distributed along both synaptic and extra-synaptic regions of the sarcolemma, although their overall levels are reduced compared with wild-type (WT) muscle. In contrast, in WT mice, utrophin is restricted to NMJs, whereas in dystrophic muscles from both mutants, it is distributed along both synaptic and extra-synaptic regions of the sarcolemma, particularly within the innervated zone of muscle fibers. As muscles mature and degeneration begins, these DGC components become highly restricted to NMJs while being markedly reduced or absent from the extra-synaptic sarcolemma in many muscle cells. Although utrophin remains highly enriched at synaptic sites in mdx:α-syn-/- muscles, their NMJs display severe structural abnormalities compared with those of mdx mice. These include a dramatic reduction in synaptic fold depth and density, a decrease in presynaptic vesicle density, retraction of nerve terminals, and axonal thinning. These findings demonstrate that utrophin localization at the NMJ is not sufficient to preserve synaptic integrity and that functional interactions between utrophin and α-syn are required to maintain the NMJ in dystrophic muscle.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 13","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13327110/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375614","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":"Circulating MYOM3 fragments reflect disease severity and therapeutic efficacy in tubular aggregate myopathy and Stormorken syndrome.","authors":"Emma Lafabrie, Céline Tard, Pascal Cintas, Agnès Ribes, Jocelyn Laporte, Johann Böhm","doi":"10.1093/hmg/ddag059","DOIUrl":"https://doi.org/10.1093/hmg/ddag059","url":null,"abstract":"<p><p>Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by muscle weakness, thrombocytopenia, spleen anomalies and short stature. They are due to mutations affecting the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1 and leading to aberrant Ca2+ homeostasis. Therapeutic approaches aiming to rebalance intracellular Ca2+ levels largely rescued the multi-systemic phenotype in Stim1R304W/+ mice harboring the most common TAM/STRMK mutation. However, the currently used biomarkers to follow disease progression are costly and inadequate for longitudinal studies. Here, we investigated the suitability of MYOM3 to serve as a robust blood-based biomarker for TAM/STRMK. Using only minimal blood volumes, we detected highly elevated circulating MYOM3 levels in plasma samples from Stim1R304W/+ mice and TAM/STRMK patients with different mutations, and we found that the MYOM3 levels were normalized in Stim1R304W/+ mice undergoing efficient therapies. We also identified skeletal muscle as the primary source of circulating MYOM3, a structural protein of the contractile unit in myofibers, and uncovered that MYOM3 is primarily expressed in regenerating muscle fibers and in fast-twitch type IIa fibers. Overall, this work emphasizes the utility of MYOM3 as a minimally-invasive biomarker for disorders involving myofiber degeneration, and highlights the ability of MYOM3 to detect early muscle dysfunction in TAM/STRMK and evaluate therapeutic efficiency.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 13","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382027","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":"A novel gene ACTRT3 mutations induce sperm malformations and fertilization failure via Acrosomal ultrastructural defects.","authors":"Zhenhan Xu, Na Lu, Jintao Guo, Linyan Lv, Yun Hu, Guihua Sun, Haicheng Chen, Linan Xu, Haitao Zeng, Guihua Liu","doi":"10.1093/hmg/ddag057","DOIUrl":"https://doi.org/10.1093/hmg/ddag057","url":null,"abstract":"<p><p>Numerous actin-related proteins (ARPs) deficiencies have been confirmed to cause sperm acrosomal structural abnormalities, representing significant genetic factors in male infertility. We identified a patient with a missense mutation in ACTRT3, who presented with teratozoospermia and experienced embryonic developmental arrest following intracytoplasmic sperm injection (ICSI). Further analysis revealed ultrastructural abnormalities in the sperm acrosome. To validate these findings, we generated a conditional knockout transgenic mouse model. Male homozygous mutant mice recapitulated the human phenotype, exhibiting consistent acrosomal ultrastructural defects, infertility, and embryonic developmental arrest. To overcome this limitation, a dual-agonist artificial oocyte activation (AOA) protocol combining ionomycin and SrCl2 was developed. This strategy successfully rescued blastocyst formation in Actrt3-deficient mouse models and enabled embryos from the affected couple to develop to the blastocyst stage after ICSI, culminating in a successful pregnancy post-transfer. The combinatorial AOA approach outperformed monotherapy by synergistically restoring PLCZ1-associated calcium signaling defects, providing a tailored solution for infertility linked to actin-related protein deficiencies.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 13","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148375617","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 FVB-nmd SMARD1 mouse presents with early respiratory deficits and pathology that significantly impact lifespan.","authors":"Roxanne Muchow, Michelle Woolridge, Catherine L Smith, Francisco J Llorente Torres, Dennis Perez-Lopez, Nicole L Nichols, Christian L Lorson, Monique A Lorson","doi":"10.1093/hmg/ddag056","DOIUrl":"10.1093/hmg/ddag056","url":null,"abstract":"<p><p>Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare, inherited genetic disease caused by mutations in the immunoglobulin mu binding protein (IGHMBP2) gene that result in spinal muscular atrophy with respiratory distress (SMARD1) or Charcot-Marie-Tooth Type 2S (CMT2S). SMARD1 clinical symptoms include respiratory failure, progressive muscular weakness, feeding deficiencies, and sensory and autonomic defects. In this paper, we examined respiration in the FVB-Ighmbp2nmd/nmd (FVB-nmd) mouse model that has an average lifespan of twenty days. The previously reported B6.BKS Ighmbp2nmd-2J/J (B6-nmd-2 J) mouse model has a variable lifespan ranging from four weeks to seven months with no respiratory distress noted until end stage; therefore, we wanted to determine whether the reduced lifespan of FVB-nmd mice was attributed to respiratory-associated changes. Our findings demonstrate that FVB-nmd mice showed severe respiratory deficiencies in nearly all parameters quantified by plethysmography. Surprisingly, the innervation status of neuromuscular junctions of respiratory and oral muscles were largely unaffected throughout the lifespan of the FVB-nmd mice. Diaphragm muscle fibers were reduced in size and the phrenic nerve demonstrated changes in fiber size and myelination. The hypoglossal nerve innervating the tongue also showed disease pathology. Assessment of lung tissue also revealed significant pathology. The investigation of the FVB-Ighmbp2nmd/nmd mouse model provides insight on how reduced IGHMBP2 protein alters respiratory function and impacts lifespan.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 13","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382015","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":"Nucleic acid-based therapeutic strategies for modulator-refractory cystic fibrosis-causing variants.","authors":"Mark D Leahy, Immacolata Zollo, Luka A Clarke, Carlos M Farinha","doi":"10.1093/hmg/ddag058","DOIUrl":"https://doi.org/10.1093/hmg/ddag058","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a life-limiting autosomal recessive disorder caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR) gene that impair epithelial chloride ion transport, leading to progressive lung dysfunction among other systemic manifestations. Small molecule CFTR modulators have dramatically improved outcomes for people with CF (pwCF) by promoting the trafficking of defective CFTR protein to the cell surface and enhancing its activity. However, a substantial proportion of pwCF harbor genotypes which remain refractory to CFTR modulators and thus lack approved disease-modifying treatments, most commonly nonsense and splicing variants that disrupt CFTR expression at the transcript or translation level. This review delineates the molecular mechanisms underlying modulator-refractory CFTR genotypes, focusing on premature termination codons, nonsense-mediated mRNA decay (NMD), and aberrant pre-mRNA splicing. We examine how these biological phenomena determine and constrain modulator efficacy while simultaneously defining therapeutic entry points. We evaluate emerging DNA-targeted strategies, such as gene replacement and gene editing, alongside RNA-directed approaches, including mRNA replacement, antisense oligonucleotides, CFTR amplifiers, translational readthrough agents and NMD inhibition. Variant-specific sensitivity, reported clinical and preclinical evidence, and practical considerations for implementation are critically assessed. By aligning molecular defect with therapeutic modality, this framework enables rational prioritization of intervention strategies for modulator-refractory CFTR genotypes.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 13","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148338434","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":"Nicotinamide riboside prevents mitochondrial dysfunction in nemaline myopathy type 6.","authors":"Rianne J Baelde, Leander A Vonk, Edgar E Nollet, Ricardo A Galli, Alexcia Fortes Monteiro, Sultan Bastu, Bornale Das, Michel van Weeghel, Bauke V Schomakers, Kasper T Vinten, Marloes van den Berg, Jolanda van der Velden, Riekelt H Houtkooper, Nicol C Voermans, Edoardo Malfatti, Coen A C Ottenheijm, Josine M de Winter","doi":"10.1093/hmg/ddag023","DOIUrl":"10.1093/hmg/ddag023","url":null,"abstract":"<p><p>Nemaline Myopathy type 6 (NEM6) is a congenital myopathy caused by variants in Kelch-repeat-and-BTB-(POZ)-Domain-Containing-13 (KBTBD13). The majority of the NEM6 patients harbor the Dutch founding variant KBTBD13R408C (c.1222C > T, p.Arg408Cys) and experience skeletal muscle weakness and sarcomere-based hypercontractility. Histological characterization of NEM6 patient biopsies by NADH staining shows the presence of cores, suggesting mitochondrial dysfunction. We aimed to elucidate the role of mitochondrial dysfunction in NEM6 pathology and tested the ability of the NAD+ precursor nicotinamide riboside (NR) to improve mitochondrial performance. We performed a natural history study in homozygous Kbtbd13R408C-knockin mice (NEM6 mouse model) to investigate the onset and progression of mitochondrial dysfunction in NEM6. We performed high-resolution respirometry, metabolic treadmill experiments and histoenzymatic NADH and SDH stainings on cryosections. Additionally, we used multi-omics analyses to investigate impacted pathways and metabolite dysregulation and performed NR supplementation for eight weeks to prevent the onset of mitochondrial dysfunction in NEM6 mice. Throughout disease progression, NEM6 mice display decreased mitochondrial respiration, impaired metabolic performance and the presence of cores with histoenzymatic reactions. Multi-omics studies revealed that the TCA cycle is heavily impacted and that NAD+ levels are decreased throughout disease progression. We aimed to restore NAD+ levels by supplementation of NR. Remarkably, NR treatment in 1-months-old NEM6 mice, prevented the onset of mitochondrial dysfunction. In conclusion, these results provide insight in the onset and progression of mitochondrial dysfunction in NEM6 and offer proof-of-concept for NR as a therapeutic strategy.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294727","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":"Retraction: Breast cancer cell-derived exosome-delivered microRNA-155 targets UBQLN1 in adipocytes and facilitates cancer cachexia-related fat loss.","authors":"","doi":"10.1093/hmg/ddag038","DOIUrl":"10.1093/hmg/ddag038","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13274299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264251","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":"Retraction: Aqua-soluble DDQ reduces the levels of Dr1 and Ab and inhibits abnormal interactions between Ab and Dr1 and protects Alzheimer's disease neurons from Ab- and Dr1-induced mitochondrial and synaptic toxicities.","authors":"","doi":"10.1093/hmg/ddag049","DOIUrl":"10.1093/hmg/ddag049","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13274298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148264256","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":"Evidence that disruption of Discoidin domain receptor 2 contributes to palate malformations through effects on the extracellular matrix.","authors":"Julia A Capecki, Helena Shkuro, Öznur Yilmaz, Lisa Schmitt, Khadija Channab, Tobias T Lindenberg, Teresa Kruse, Sarah Achterrath, Berta Crespo, Anna Siewert, Mostafa Bakhshi, Leandra Pantel, Kerstin U Ludwig, Matthias Geyer, Elisabeth Mangold, Benjamin Odermatt, Nina Ishorst","doi":"10.1093/hmg/ddag052","DOIUrl":"10.1093/hmg/ddag052","url":null,"abstract":"<p><p>Orofacial clefting (OFC) is among the most common birth defects and can occur either as part of a syndrome or in isolation (nonsyndromic, ns). Cleft palate only (CPO) is an OFC subtype. Here, we searched for novel nsCPO risk genes carrying homozygous and compound-heterozygous variants, by analyzing exome data from six sibling pairs with nsCPO born to unaffected parents. After stringent quality control and filtering, we identified 6 homozygous variants and 32 compound-heterozygous variants in 5 and 16 candidate genes, respectively. We prioritized DDR2, a collagen-activated receptor-tyrosine-kinase influencing extracellular matrix composition, as our top candidate for functional follow-up, since variants in this gene can cause Warburg-Cinotti syndrome, the phenotypic spectrum of which includes palatal abnormalities. Knock-down and knock-out of DDR2-orthologs in zebrafish caused craniofacial abnormalities resembling CPO in humans. Zebrafish immunostaining indicated that DDR2-orthologs were expressed in mature head muscle cells, while murine single-cell RNA-Sequencing data detected Ddr2 expression only in head muscle progenitor cells; the latter finding was confirmed in human embryo sections stained for DDR2. DDR2-expressing head muscle progenitor cells may influence extracellular matrix composition through DDR2-mediated signaling, thereby affecting outgrowth, elevation, and fusion of the palatal shelves, a previously postulated mechanism involved in palatogenesis. Most established OFC genes (e.g. CDH1, CTNND1, IRF6, and GRHL3) act via mechanisms related to epithelial integrity and periderm differentiation, whereas our data provide evidence supporting DDR2 as a risk gene for nsOFC that functions by influencing extracellular matrix composition.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148294748","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":"Editor's Note: Protective effects of antidepressant citalopram against abnormal APP processing and amyloid beta-induced mitochondrial dynamics, biogenesis, mitophagy and synaptic toxicities in Alzheimer's disease.","authors":"","doi":"10.1093/hmg/ddag051","DOIUrl":"10.1093/hmg/ddag051","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":"35 12","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13261670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148224868","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}