Journal of Human Genetics最新文献

{"title":"A copy number variant overlapping the 3'UTR of PLP1 causes spastic paraplegia.","authors":"Malak Alghamdi, Essa Alharbi, Salman Aljarallah, Ghaida Alghamdi, Reham M Balahmar, Nisserin Jado, Hebattalah Hamed, Dima Jamjoom, Fahad A Bashiri, Naif A M Almontashiri","doi":"10.1038/s10038-025-01340-2","DOIUrl":"10.1038/s10038-025-01340-2","url":null,"abstract":"<p><p>Leukodystrophy presents a significant diagnostic challenge due to its varied clinical presentation and similarity to other myelin disorders, characterized by abnormalities in myelin and white matter. Hypomyelination disorders, including Pelizaeus-Merzbacher disease (PMD) and hereditary spastic paraplegias (SPG), are associated with variants in the proteolipid protein 1 (PLP1) gene, leading to symptoms ranging from severe dysmyelination in infancy to delayed dysmyelination and axonal degeneration in adulthood. Family history was taken, and pedigree was constructed. Recruitment included seven males and females with spastic paraplegia and nine healthy relatives, who were clinically investigated, and tested with molecular genetic assays including whole exome sequencing (WES), whole genome sequencing (WGS), and PCR amplification with fragment analysis on gel electrophoresis to identify and confirm the genetic cause. Family history was consistent with hereditary condition marked by progressive spastic paraplegia in 10 family members. Males had early onset and progressive paraplegia, and neurodegenerative conditions, resulting in a decline in the neurocognitive functions. However, in some females, the symptoms manifested later in their 30s-40s, leading to neurodegenerative conditions and spastic paraplegias. A total of 16 family members were available for genetic testing and segregation studies. Initial clinical WES in four members was negative. Next, WGS identified a novel copy number variant (CNV) loss (75.5 kb) involving the 3'UTR of the PLP1 gene in three members (the mother, affected son, but not in the unaffected son). Segregation studies in all 16 family members confirmed the presence of the CNV in five additional affected individuals and an asymptomatic female, but not in the eight asymptomatic individuals. Our study reports a novel 3'UTR CNV in PLP1 in a large family with several individuals affected with SPG. This finding expands the mutational landscape of the PLP1-related diseases to include CNV and, possibly, small sequence changes in the regulatory regions of PLP1, that would otherwise be overlooked during the interpretation of the next generation sequencing data.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"365-370"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143811478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variant sub-tiering, disease-gene associations and strictness of clinical criteria improves the interpretation of variants of uncertain significance in hereditary cardiomyopathies and rhythm disorders.","authors":"Marco Castori, Sandra Mastroianno, Andrea Fontana, Silvia Morlino, Grazia Nardella, Ester Di Muro, Pietro Palumbo, Maria Pia Leone, Riccardo Pracella, Orazio Palumbo, Antonio Petracca, Domenico Rosario Potenza, Massimo Carella, Giovanni De Luca, Carlo Coli, Raimondo Salvatore Massaro, Rosa De Santis, Lorenzo Vaccaro, Marcella Cesana, Davide Cacchiarelli, Massimiliano Copetti, Carmela Fusco, Giuseppe Di Stolfo","doi":"10.1038/s10038-025-01344-y","DOIUrl":"10.1038/s10038-025-01344-y","url":null,"abstract":"<p><p>Besides the ClinGen's efforts to standardize the ACMG/AMP criteria and European initiatives aimed at monitoring quality standards, molecular diagnostics of hereditary cardiomyopathies and heart rhythm disorders (HCHRDs) remains strongly influenced by the local strategies developed to overcome the variables in which genetic testing is requested. This is a monocentric study on the clinical and molecular findings of 363 pedigrees with various HCHRDs. ACMG/AMP criteria were adapted according to the ClinGen's material and internal specifications. Phenotypes were reviewed according to known disease-gene associations and the concurrence of multiple variants in the same individual. Relatives were studied when available and the significance of selected variants was supported by RNA- studies before reporting. One or more (likely) pathogenic variants were found in 80 pedigrees (22.0%), while 96 (26.4%) displayed one or more variants of uncertain significance (VUS) only. The 132 identified VUS were sub-tiered according to the Bayesian score in three categories presenting distinguishable patterns of selected criteria. VUS_high showed profiles of key molecular criteria and resembled deleterious variants according to the combinations of assigned criteria, while the VUS_low category displayed a high chance of conflicting combinations of criteria and unsupported disease-gene associations. Reclassification to likely pathogenic by the application of applicable clinical criteria (PVS1_Strength, PP1 and PP4) was accessible to VUS_high and a few VUS_mid only. This work supports the combined need to (i) introduce VUS sub-tiering, (ii) consider known disease-gene associations, (iii) stringently apply clinical criteria and (iv) incorporate RNA data to improve the clinical significance of genetic testing in HCHRDs.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"349-358"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPD1 deficiency-a rare, overlooked cause of liver disease.","authors":"Necati Emrecan Türk, Serkan Belkaya, Selçuk Teke, Ceyda Tuna Kırsaçlıoğlu, Fatma Tuba Eminoğlu, Tunahan Çalıkoğlu, Aydan Kansu, Zarife Kuloglu","doi":"10.1038/s10038-025-01339-9","DOIUrl":"10.1038/s10038-025-01339-9","url":null,"abstract":"<p><p>Transient infantile hypertriglyceridemia is one of the diseases that should be considered in case of unexplained elevated liver enzymes, hypertriglyceridemia and hepatosteatosis. We report 2 siblings with novel homozygous variants in the GPD1 gene with transient infantile hypertriglyceridemia. Two siblings born from consanguineous marriage were referred due to hepatomegaly, elevated transaminases and fatty liver. After excluding other possible causes of fatty liver and elevated transaminase levels; whole-exome sequencing (WES) was performed on genomic DNA isolated from the peripheral blood samples of both patients. Whole exome sequencing revealed the identification of a novel homozygous variant, c.628 G > C:p.G210R, in GPD1. Our report underscores the importance of genome sequencing in diagnosing unexplained childhood fatty liver disease and/or elevated enzyme levels. In patients with transient infantile hypertriglyceridemia, investigation into novel homozygous variants in the GPD1 gene should be conducted using whole exome sequencing.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"375-379"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of MCCC1 expression by a Parkinson's disease-associated intronic variant: implications for pathogenesis.","authors":"Shunsaku Sogabe, Hiroko Nakano, Yusuke Ogasahara, Pei-Chieng Cha, Yuko Ando, Mariko Taniguchi-Ikeda, Ryusaku Matsumoto, Motoi Kanagawa, Kazuhiro Kobayashi, Shigeo Murayama, Takashi Aoi, Tatsushi Toda, Wataru Satake","doi":"10.1038/s10038-025-01335-z","DOIUrl":"10.1038/s10038-025-01335-z","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a common neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. While some familial cases result from single-gene mutations, most are sporadic, involving complex genetic and environmental interactions. Among PD risk loci identified through genome-wide association studies, MCCC1 encodes a mitochondrial enzyme essential for leucine catabolism; however, the causal variant remains unclear. Here, we investigated whether the intronic variant rs12637471 regulates MCCC1 mRNA expression and influences PD risk. Postmortem brain analysis revealed significantly elevated MCCC1 mRNA levels in G-allele carriers, consistent with peripheral tissue eQTL data from GTEx. Using CRISPR/Cas9-edited induced pluripotent stem cells, we generated isogenic lines differing only at rs12637471 and observed increased MCCC1 expression in G-allele dopaminergic neurons. Given MCCC1's mitochondrial role, its dysregulation may impact mitochondrial homeostasis, autophagy, or inflammation, potentially contributing to PD pathogenesis.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"371-374"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hemizygous SMARCA1 variants cause X-linked intellectual disability.","authors":"Naoto Nishimura, Takeshi Mizuguchi, Keisuke Hamada, Kotaro Yuge, Masamune Sakamoto, Naomi Tsuchida, Yuri Uchiyama, Atsushi Fujita, Eriko Koshimizu, Kazuharu Misawa, Satoko Miyatake, Yoriko Watanabe, Hitoshi Osaka, Koh-Ichiro Yoshiura, Kazuhiro Ogata, Naomichi Matsumoto","doi":"10.1038/s10038-025-01346-w","DOIUrl":"10.1038/s10038-025-01346-w","url":null,"abstract":"<p><p>Pathogenic SNF2 related chromatin remodeling ATPase 1 (SMARCA1) variants have been reported in patients with X-linked intellectual disability (XLID) characterized by macrocephaly and variable neurological symptoms. Here, we report two unrelated male patients with XLID due to novel SMARCA1 variants detected by exome sequencing. Patient 1 showed macrocephaly, behavioral difficulty, and learning disability with a hemizygous SMARCA1 variant (NM_003069.5:c.1795 C > T p.[Gln599*]) leading to nonsense-mediated decay. Patient 2 had ataxia and speech delay with a hemizygous missense variant (NM_003069.5:c.1343 G > T p.[Arg448Leu]). Structural modeling suggested that the missense variant, p.(Arg448Leu) might destabilize interactions between SMARCA1 and nucleosomal DNA, thereby contributing to the abberant effect of mutant SMARCA1 protein. Both variants were inherited from their unaffected healthy mothers. This study suggests that hemizygous variants impairing SMARCA1 function can cause XLID with other variable features, such as macrocephaly and ataxia, in men.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"359-363"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated serum autotaxin levels and multiple system atrophy-like presentation in a patient with PLA2G6-associated neurodegeneration.","authors":"So Okubo, Takashi Matsukawa, Norifumi Kawamoto, Masahiko Tsujita, Kenta Orimo, Hiroya Naruse, Jun Mitsui, Masashi Hamada, Wataru Satake, Tatsushi Toda","doi":"10.1038/s10038-025-01342-0","DOIUrl":"10.1038/s10038-025-01342-0","url":null,"abstract":"<p><p>PLA2G6-associated neurodegeneration (PLAN) encompasses a spectrum of phenotypes caused by biallelic pathogenic variants in PLA2G6. Initially linked to infantile and atypical neuroaxonal dystrophy, PLAN now includes adult-onset conditions such as dystonia-parkinsonism, ataxia, and spastic paraplegia. We report a female patient presenting young-onset parkinsonism with pyramidal tract signs, cerebellar atrophy, and autonomic dysfunction, mimicking multiple system atrophy (MSA). Neuroimaging showed decreased dopamine uptake and cerebellar hypoperfusion. Genetic analysis identified a homozygous pathogenic variant in PLA2G6 (c.967G>A, p.Val323Met), confirming a diagnosis of PLAN. Interestingly, elevated serum autotaxin levels (4.67 ng/mL) without liver abnormalities. Bilateral brachymetatarsia was also observed, which may indicate an association with the PLA2G6 variant. This case underscores the importance of considering PLAN in cases of young-onset parkinsonism with multisystem involvement. Genetic testing is crucial for accurate diagnosis and management of such cases. Elevated serum autotaxin levels may be associated with decreased phospholipase activity in PLAN and warrants further investigation.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"381-384"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A random forest-based predictive model for classifying BRCA1 missense variants: a novel approach for evaluating the missense mutations effect.","authors":"Hamed Ka, Maryam Naghinejad, Akbar Amirfiroozy, Mohd Shahir Shamsir, Sepideh Parvizpour, Jafar Razmara","doi":"10.1038/s10038-025-01341-1","DOIUrl":"10.1038/s10038-025-01341-1","url":null,"abstract":"<p><p>The right classification of variants is the key to pre-symptomatic detection of disease and conducting preventive actions. Since BRCA1 has a high incidence and penetrance in breast and ovarian cancers, a high-performance predictive tool can be employed to classify the clinical significance of its variants. Several tools have previously been developed for this purpose which poorly classify the significance in specific cases. The proposed tools commonly assign a score without providing any interpretation behind it. To reach an accurate predictive tool with interpretation abilities, in this study, we propose BRCA1-Forest which works based on random forest as a well-known machine learning technique for making interpretable decisions with high specificity and sensitivity in variants classification. The method involves narrowing down available options until reaching the final decision. To this end, a set of BRCA1 benign and pathogenic missense variants was collected first, and then, the dataset was prepared based on the effect of each variant on the protein sequence. The dataset was enriched by adding physicochemical changes and the conservation score of the amino acid position as pathogenicity criteria. The proposed model was trained based on the dataset to classify the clinical significance of variants. The performance of BRCA1-Forest was compared to four state-of-the-art methods, SIFT, PolyPhen2, CADD, and DANN, in terms of different evaluation metrics including precision, recall, false positive rate (FPR), the area under the receiver operator curve (AUC ROC), the area under the precision-recall curve (AUC-PR), and Mathew correlation coefficient (MCC). The results reveal that the proposed model outperforms the abovementioned tools in all metrics except for recall. The software of BRCA1-Forest is available at https://github.com/HamedKAAC/BRCA1Forest .</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"341-348"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143995771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level.","authors":"Boudour Khabou, Houcemeddine Othman, Manel Guirat, Imen Chabchoub, Sana Kmiha, Bahri Mahjoub, Rania Abdelhadi, Afif Ben Mahmoud, Rim Kallel, Tahya Sellami Boudawara, Thouraya Kammoun, Faiza Fakhfakh, Hassen Hadj Kacem, Hassen Kammoun","doi":"10.1038/s10038-025-01338-w","DOIUrl":"10.1038/s10038-025-01338-w","url":null,"abstract":"<p><p>PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":"331-339"},"PeriodicalIF":2.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microcephaly-related global developmental delay caused by a pathogenic METTL5 splicing mutation in a Chinese family.","authors":"Xiaoyan Zhou, Congcong Teng, Wenjing Zhao, Wen Yang, Yuecheng Yang, Qing Chen, Ming He, Jie Zhang","doi":"10.1038/s10038-025-01354-w","DOIUrl":"https://doi.org/10.1038/s10038-025-01354-w","url":null,"abstract":"<p><p>Microcephaly-related global developmental delay (GDD) and intellectual disability (ID) are characterized by a broad spectrum of neurodevelopmental impairments and encompass a multitude of causal factors. METTL5, a critical component involved in 18S rRNA methylation, has garnered considerable attention owing to its pivotal role in the pathogenesis of GDD and ID associated with microcephaly. A comprehensive physical examination and developmental assessment were performed for a 2-year-old girl presenting with symptoms of GDD and primary microcephaly. Whole-exome sequencing (WES) was performed to identify the pathogenic variant, and Sanger sequencing confirmed the mutation. To further investigate the pathogenicity of the mutation, minigene splicing assays, in vivo RT-PCR and bioinformatics analysis were employed. The WES identified a METTL5 homozygous intron mutation (NM_014168.4: c.224+5 G > A) in the proband. Sanger sequencing further validated the mutation in the family. Minigene assays and in vivo RT-PCR assays demonstrated exon 2 skipping, resulting in a 115-bp deletion in the mutated sequence. Bioinformatics analysis confirmed the pathogenicity of the mutation. For the first time, this study reported that a homozygous mutation (c.224+5 G > A) in the METTL5 gene led to microcephaly-related GDD in a Chinese family. Meantime, the report has validated the pathogenicity of intronic mutations and expanded the mutational spectrum of the METTL5 gene. Thus, this study aids our understanding of the role of METTL5 in GDD and provides a theoretical foundation for the prevention of this disease.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of different promoters in lentiviral vectors for expression of the N-acetyl-galactosamine-6-sulfate sulfatase gene.","authors":"Betul Celik, Andrés Felipe Leal, Shaukat Khan, Shunji Tomatsu","doi":"10.1038/s10038-025-01353-x","DOIUrl":"https://doi.org/10.1038/s10038-025-01353-x","url":null,"abstract":"<p><p>Mucopolysaccharidosis IVA (MPS IVA) is caused by pathogenic variants in the GALNS gene encoding N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, leading to glycosaminoglycan (GAG) accumulation in multiple tissues, resulting in progressive skeletal dysplasia and poor quality of life. There is currently no effective treatment for this skeletal disease. This study proposes a novel lentiviral vector (LV)-based gene therapy that produces and secretes the active GALNS enzyme at supraphysiologic levels within the cells. LVs carrying the native GALNS encoding sequence (cDNA) were made under three different promoters: CBh, COL2A1, and CD11b. Moreover, we designed LVs carrying the native GALNS cDNA tagged with D8 octapeptide under the CD11b promoter and a human codon-optimized GALNS cDNA under the CBh promoter, respectively. Transduced HEK293 cells, HepG2 cells, and MPS IVA fibroblasts and chondrocytes were cultured for 8 and 30 days, and the media were collected every three days. The enzyme activity, GAG levels, and vector copy numbers (VCNs) in these cells and media were analyzed. LV with the COL2A1 promoter produced the highest enzyme activity in HEK293, HepG2, MPS IVA fibroblasts, and chondrocytes, followed by LV with the CBh promoter. VCNs were higher in MPS IVA fibroblasts treated with LV-CBh-hGALNS and in HepG2 cells treated with LV-CD11b-hGALNS than in HEK293 cells. Accumulated GAGs were normalized to wild-type levels by the LV gene therapy, especially with CBh and COL2A1 promoters. These findings, if further validated, could significantly impact the treatment of MPS IVA, offering a more effective and feasible treatment option.</p>","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}