Molecular genetics and metabolism最新文献

{"title":"Biochemical investigation of pathogenic missense mutations of human 4-amino butyrate aminotransferase towards the understanding of the molecular pathogenesis of GABA transaminase deficiency.","authors":"Giulia Ambrosini ,&nbsp;Fulvio Floriani ,&nbsp;Vittoria Manni,&nbsp;Ilaria Dando,&nbsp;Riccardo Montioli","doi":"10.1016/j.ymgme.2025.109149","DOIUrl":"10.1016/j.ymgme.2025.109149","url":null,"abstract":"<div><div>Gamma-amino butyrate aminotransferase (GABA-AT or ABAT) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the conversion of GABA and α-ketoglutarate into succinic semialdehyde and L-glutamate. In humans, the primary physiological role of GABA-AT is to control the level of GABA in neuronal tissues. Mutations on <em>ABAT</em> gene are associated to GABA-AT deficiency, an ultra-rare autosomal recessive disorder characterized by accelerated linear growth, severe psychomotor retardation, seizures, hypotonia, and hyperreflexia. So far, several missense pathogenic mutations of GABA-AT have been identified; however, their molecular effects at protein level have been poorly investigated. In this work a biochemical characterization of 10 pathogenic variants of human GABA-AT was carried out by expressing the protein in HEK-293 cells. Moreover, <em>in-silico</em> analyses of the variants were performed to corroborate the experimental findings. Altogether, the data obtained on protein expression level, GABA transaminase activity, and the predicted structural impact allowed us to classify the variants into three distinct groups, such as: (i) variants with strong structural and catalytic defects (p.P152S, p.L211F, and p.L478P); (ii) variants characterized mainly by a strong catalytic defect (p.R220K, p.Q296H, and p.R377W); (iii) variants exhibiting moderate structural and catalytic defects maintaining substantial transaminase activity (p.R92Q, p.F213C, p.G465D, and p.G465R). Based on these results, we provide a picture of the molecular defects of different GABA-AT pathogenic variants with the aim of gaining insights into the enzymatic phenotypes in GABA-AT deficiency.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109149"},"PeriodicalIF":3.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123837","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":"Newborn screening for metachromatic leukodystrophy: Preparation of reagents and methodology for measurement of sulfatides and arylsulfatase A enzymatic activity in dried blood spots","authors":"Austin Shaff ,&nbsp;Khaja Basheeruddin ,&nbsp;Soumeya Bekri ,&nbsp;Heather A. Brown ,&nbsp;Heather J. Church ,&nbsp;Justin Gianares ,&nbsp;Xinying Hong ,&nbsp;Simon A. Jones ,&nbsp;Tate Kappell ,&nbsp;Francyne Kubaski ,&nbsp;Petra Oliva ,&nbsp;Joseph Orsini ,&nbsp;Abdellah Tebani ,&nbsp;Teresa H.Y. Wu ,&nbsp;Gojko Lalic ,&nbsp;Michael H. Gelb","doi":"10.1016/j.ymgme.2025.109138","DOIUrl":"10.1016/j.ymgme.2025.109138","url":null,"abstract":"<div><div>Ex vivo gene therapy combined with haemapoietic stem cell transplant has recently been approved in Europe and the USA for treatment of metachromatic leukodystrophy (MLD). Since treatment is only efficacious if carried out in the pre-symptomatic or minimally-symptomatic phases, newborn screening (NBS) for MLD is warranted. MLD NBS is being developed worldwide through the International MLD Newborn Screening Alliance. Screening is carried out by measurement of the elevation of two sulfatide molecular species, 16: 0- and 16:1-OH-sulfatide in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A (ARSA) enzymatic activity in the same DBS. After 2–3 years of NBS assay development including pilot studies, members of the International MLD Newborn Screening Alliance arrived at a consensus set of assay protocols. In this article, we provide these protocols with full details so that the methods can be readily adopted by additional NBS laboratories. We also provide the full details of preparation of the required reagents.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109138"},"PeriodicalIF":3.7,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134201","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":"Sphingolipid de novo synthesis is upregulated in a macrophage model of Gaucher disease","authors":"Ashleigh Lake ,&nbsp;Jennifer Saville ,&nbsp;Maria Fuller","doi":"10.1016/j.ymgme.2025.109139","DOIUrl":"10.1016/j.ymgme.2025.109139","url":null,"abstract":"<div><div>Gaucher disease (GD) is an inborn error of sphingolipid metabolism characterised by a block in the lysosomal degradation of glucosylceramide (GlcCer), which consequently accumulates in the lysosomes of affected cells. The product of GlcCer degradation is ceramide, and it is reasonable to expect that there would be a reduction in ceramide in GD, but there is conflicting evidence in different cells and tissues. Using a stable isotope ¹³C₁₆-palmitate labelling method, we sought to investigate the impact of the block in GlcCer degradation on the sphingolipid metabolic pathway in a conduritol B epoxide (CBE)-induced GD macrophage model. Liquid chromatography-mass spectrometry was used to measure acyl-, base-, and dual-labelled sphingolipid ‘heavy’ ¹³C₁₆ isotopologues which were distinguished by their incorporation of ¹³C₁₆ into the acyl chain, sphingoid base, or both, respectively. Base- and dual-labelled C16:0 ceramide was consistently elevated in CBE-GD macrophages whereas base- and acyl-labelled C24:0 ceramide was unchanged or decreased, suggesting a preference for ¹³C₁₆-palmitate in the sphingolipid <em>de novo</em> pathway over acyl elongation. Confirmation of the ¹³C₁₆-palmitate labelling results was then assessed with the sphingolipid <em>de novo</em> intermediate, sphinganine (d17:0), which also showed elevation of base-labelled C16:0 ceramide in CBE-GD macrophages and no change in base-labelled C24:0 ceramide. As palmitate and sphinganine are both precursors of ceramide <em>de novo</em> synthesis, all base- and dual-labelled ceramides can be accurately assigned as strictly <em>de novo</em>-derived. Therefore, we show that stable isotope ¹³C₁₆-palmitate labelling can detect alterations in the sphingolipid pathway and conclude that <em>de novo</em> synthesis is upregulated in the CBE-GD macrophage model. This upregulation is likely a compensatory mechanism employed by the CBE-GD macrophage to maintain ceramide homeostasis, following the loss of its generation through GlcCer turnover.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109139"},"PeriodicalIF":3.7,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123834","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":"Expanding the clinical phenotype and understanding the biochemical consequences of Muscle Glycogen Synthase Deficiency (GSD0B)","authors":"A. Llauradó ,&nbsp;T. Pinós ,&nbsp;M. Codina-Solà ,&nbsp;E. Martínez-Saez ,&nbsp;J.L. Restrepo-Vera ,&nbsp;M. Salvadó ,&nbsp;D. Sanchez-Tejerina ,&nbsp;J. Sotoca ,&nbsp;P. Muñoz ,&nbsp;E. Rovira-Moreno ,&nbsp;Leyla Büyükdereli ,&nbsp;E. Garcia-Arumi ,&nbsp;J.M. Vidal-Taboada ,&nbsp;D. Ovelleiro ,&nbsp;R. Juntas-Morales","doi":"10.1016/j.ymgme.2025.109140","DOIUrl":"10.1016/j.ymgme.2025.109140","url":null,"abstract":"<div><h3>Aims</h3><div>Glycogen storage disease type 0b (GSD 0b) is an exceptionally rare metabolic disorder caused by biallelic pathogenic variants in the <em>GYS1</em> gene, leading to deficient glycogen synthase (GS) activity. In 2022, two cases were reported for the first time with a phenotype presenting as adult-onset myopathy.</div></div><div><h3>Methods</h3><div>A 56-year-old woman with a history of progressive limb-girdle and axial weakness was evaluated. Clinical assessments, muscle biopsy, genetic analyses, RNA sequencing from muscle tissue, and western blot analyses were performed. Muscle glycogen levels were quantified using spectrophotometry.</div></div><div><h3>Results</h3><div>The patient was found to have a biallelic pathogenic variant (c.678 + 1G &gt; A) in the <em>GYS1</em> gene. Skeletal muscle MRI showed a distinctive pattern with potential diagnostic value. Transcriptome sequencing indicated that the variant caused skipping of exon 4 in half of the transcripts and retention of intron 4 in the remainder. Muscle biopsy revealed marked glycogen depletion. In our study, we have also observed the molecular and biochemical consequences resulting from the presence of pathogenic variants in the <em>GYS1</em> gene. Glycogen quantification confirmed a significant reduction in muscle glycogen content. Our findings elucidate the molecular consequences of <em>GYS1</em> deficiency, showing severely reduced GS protein levels, leading to compensatory decreases in glycogen degradation (PHKA1, PHKB, PHKG1 and AGL) and glycolytic (PFKM, PKM1 and the phosphorylated form of pPDHE) enzymes. Additionally, the absence of GS affects STBD1 and prompts a shift towards oxidative metabolism due to reduced glycogen levels.</div></div><div><h3>Conclusion</h3><div>This case of GSD 0b, caused by a novel <em>GYS1</em> variant, highlights the disease's clinical and molecular heterogeneity. Understanding the molecular consequences of GS deficiency can aid in developing management strategies for GSD 0b.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109140"},"PeriodicalIF":3.7,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099816","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":"An obituary and tribute to Doug Kerr","authors":"Daniel Kerr ,&nbsp;Shawn E. McCandless ,&nbsp;Stephen Cederbaum","doi":"10.1016/j.ymgme.2025.109137","DOIUrl":"10.1016/j.ymgme.2025.109137","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109137"},"PeriodicalIF":3.7,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072700","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":"Letter to the Editors: Concerning “SSR4-CDG, an ultra-rare X-linked congenital disorder of glycosylation affecting the TRAP complex: Review of 22 affected individuals including the first adult patient” by Johnsen et al.","authors":"Alessandra Verde ,&nbsp;Maria Rosa Cutri' ,&nbsp;Federica Pagani ,&nbsp;Alba Pilotta ,&nbsp;Lorenzo Pinelli ,&nbsp;Alessia Asaro ,&nbsp;Luca Cattaneo ,&nbsp;Raffaele Badolato ,&nbsp;Enza Maria Valente ,&nbsp;Jessica Galli","doi":"10.1016/j.ymgme.2025.109136","DOIUrl":"10.1016/j.ymgme.2025.109136","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109136"},"PeriodicalIF":3.7,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942373","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":"Long-term enzyme replacement therapy: Findings from the mucopolysaccharidosis VI clinical surveillance program after 15 years follow-up","authors":"Barbara K. Burton ,&nbsp;Paul R. Harmatz ,&nbsp;Veronika Horvathova ,&nbsp;Alice Lail ,&nbsp;Christina Lampe ,&nbsp;Rossella Parini ,&nbsp;Reena Sharma ,&nbsp;Elisa Leão Teles","doi":"10.1016/j.ymgme.2025.109135","DOIUrl":"10.1016/j.ymgme.2025.109135","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the long-term real-world efficacy and safety of galsulfase enzyme replacement therapy (ERT) in patients enrolled in the mucopolysaccharidosis (MPS) VI Clinical Surveillance Program (CSP).</div></div><div><h3>Methods</h3><div>The CSP collected long-term observational data of routine clinical and laboratory assessments from 30 June 2005 to 01 May 2020. Outcomes included urinary glycosaminoglycan (uGAG) level, 6-min walk test (6MWT), forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), anthropometrics and adverse events.</div></div><div><h3>Results</h3><div>The final analysis population included 221 participants with MPS VI; 212 participants received ERT (median ERT exposure time 11.7 years). In ERT-treated participants with both baseline and follow-up data, uGAG levels decreased by a mean of 59.7 % after a mean follow-up of 8.0 years (<em>P</em> &lt; 0.0001; <em>n</em> = 84), 6MWT distance increased by a mean (SE) of 42.3 (21.81) meters after a mean follow-up of 7.0 years (<em>P</em> = 0.0610, <em>n</em> = 35), FEV₁ increased by 0.36 (0.098) L after 6.5 years (<em>P</em> = 0.0014, <em>n</em> = 24), and FVC increased by 0.52 (0.143) L after 6.3 years (<em>P</em> = 0.0013, <em>n</em> = 25). Improvements were seen across subgroups of participants with high and low baseline uGAG levels (&gt;200 and ≤ 200 μg/mg creatinine). 6MWT and pulmonary function increased primarily in participants younger than 18 years at baseline while older patients showed stabilization. Galsulfase was generally well tolerated with no new safety signals identified. Most adverse events were MPS-related clinical manifestations and considered not related to galsulfase by investigators.</div></div><div><h3>Conclusions</h3><div>Data collected in the CSP over 15 years provide real-world evidence for sustained improvements in endurance and pulmonary function among patients with MPS VI treated with ERT, with no new safety concerns identified. These results further support and confirm observations from the clinical trials and previous findings from the CSP.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109135"},"PeriodicalIF":3.7,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144072699","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":"State of the art management practices for liver glycogen storage disorders: Results from an international survey among metabolic centres","authors":"Sarah C. Grünert ,&nbsp;Terry G.J. Derks ,&nbsp;Alessandro Rossi","doi":"10.1016/j.ymgme.2025.109129","DOIUrl":"10.1016/j.ymgme.2025.109129","url":null,"abstract":"<div><h3>Background</h3><div>Liver glycogen storage disorders (GSDs) are rare inherited disorders of carbohydrate metabolism that are clinically characterized by hepatomegaly and fasting intolerance. This group of disorders comprises GSD Ia and Ib as well as the so-called ketotic GSDs including GSD III, VI, IX, XI and 0a. Although clinical practice guidelines exist for most GSD subtypes, diagnostics, treatment and monitoring differ significantly among metabolic centres. The aim of this study was to gain insight into current clinical practice for liver GSDs.</div></div><div><h3>Methods</h3><div>An international web-based survey was performed among health care professionals involved in the care of individuals with liver GSDs.</div></div><div><h3>Results</h3><div>Sixty-seven respondents from 28 different countries caring for approximately 2650 liver GSD patients completed the survey. While the diagnostic approach was generally consistent, significant differences among metabolic centres are still observed with respect to monitoring parameters and treatment approaches. Reasons for these differences are local availability of management tools and treatment options, the rarity of the different GSD subtypes, the experiences of health care professionals, and the existence of extreme phenotypes.</div></div><div><h3>Conclusion</h3><div>The development of a standard set of outcomes for patients with liver GSDs is warranted as a reference for both daily care and the evaluation of safety and efficacy of future therapies. For various parameters that serve as valuable outcome measures, tools and target values should be better defined.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109129"},"PeriodicalIF":3.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147859","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":"Dual pathogenic mechanisms in lysinuric protein intolerance: Interplay between hyperammonemia and cellular metabolic dysregulation in astrocyte injury","authors":"Keisuke Kakisaka ,&nbsp;Takuro Sato ,&nbsp;Yasunori Wada ,&nbsp;Hiroaki Abe ,&nbsp;Shizuka Abe ,&nbsp;Ai Shimodate ,&nbsp;Takuya Watanabe ,&nbsp;Tokio Sasaki ,&nbsp;Yudai Fujiwara ,&nbsp;Tamami Abe ,&nbsp;Akiko Suzuki ,&nbsp;Kei Endo ,&nbsp;Yuichi Yoshida ,&nbsp;Takayoshi Oikawa ,&nbsp;Kei Sawara ,&nbsp;Akio Miyasaka ,&nbsp;Shohei Komaki ,&nbsp;Atsushi Shimizu ,&nbsp;Ken Ishikawa ,&nbsp;Manami Akasaka ,&nbsp;Takayuki Matsumoto","doi":"10.1016/j.ymgme.2025.109134","DOIUrl":"10.1016/j.ymgme.2025.109134","url":null,"abstract":"<div><h3>Background</h3><div>Lysinuric protein intolerance (LPI) is a rare genetic disorder characterized by an inherited defect in cationic amino acid transport caused by pathogenic variants in the <em>SLC7A7</em> gene. While LPI causes systemic complications, the underlying cellular mechanisms remain poorly understood. This study investigated the cellular characteristics of LPI, focusing on intracellular metabolite profiles and astrocyte response to hyperammonemia.</div></div><div><h3>Objectives</h3><div>To examine intracellular metabolite changes in LPI patients and to evaluate the response of patient-derived astrocytes to ammonia exposure.</div></div><div><h3>Methods</h3><div>Peripheral blood mononuclear cells (PBMCs) from three LPI patients and three healthy controls were analyzed for intracellular metabolite profiles using capillary electrophoresis-fourier transform mass spectrometry. Induced pluripotent stem cells were generated from a patient's PBMCs and differentiated into astrocytes. We evaluated LPI-astrocytes and their response to ammonia treatment by RNA sequencing, gene expression profiling, and cell viability assays.</div></div><div><h3>Results</h3><div>Metabolite analysis revealed significant intracellular metabolite imbalances in LPI patients, with increases of 21 metabolites including 11 amino acids. LPI-astrocytes exhibited distinct cellular characteristics regarding altered gene expression and enhanced cell cycle progression. When exposed to ammonia, the astrocytes demonstrated markedly lower cell viability and increased reactive oxygen species (ROS) production compared to control astrocytes. <em>N</em>-acetylcysteine supplementation significantly ameliorated ammonia-induced cytotoxicity.</div></div><div><h3>Conclusions</h3><div>SLC7A7 dysfunction leads to intracellular metabolite disturbances and an increase in vulnerability to ammonia toxicity through ROS production of astrocyte, suggesting hyperammonemia and amino acid deficiencies as potential therapeutic targets in LPI patient care.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109134"},"PeriodicalIF":3.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143931708","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":"Combining clinically benign IDUA variants in cis reduces enzymatic activity of the resulting enzyme within the pathogenic range","authors":"Seok-Ho Yu,&nbsp;Laura Pollard,&nbsp;Heather Flanagan-Steet,&nbsp;Richard Steet","doi":"10.1016/j.ymgme.2025.109131","DOIUrl":"10.1016/j.ymgme.2025.109131","url":null,"abstract":"<div><div>Interpretation of genotypes with multiple variants can be challenging as independent effects of each variant must be determined to predict the overall outcome for biallelic conditions. This is especially difficult when two or more variants exist <em>in cis</em> on a single allele. We used an established functional platform to characterize the impact of different clinically benign <em>IDUA</em> variants alone, or in combination, demonstrating that the relative specific activity of <em>in cis</em> variant combinations is comparable to individual variants associated with attenuated or even severe MPSI. These results reinforce the concept that combinations of otherwise clinically benign variants can produce pathogenic consequences.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109131"},"PeriodicalIF":3.7,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143934915","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}