Molecular genetics and metabolism最新文献

{"title":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00153-2","DOIUrl":"10.1016/S1096-7192(25)00153-2","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109162"},"PeriodicalIF":3.7,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144230184","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":"Clinical, metabolic, and genetic characteristics of 42 children with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency in China","authors":"Yang Liu ,&nbsp;Danmin Shen ,&nbsp;Tianyu Song ,&nbsp;Chaolong Xu ,&nbsp;Xin Duan ,&nbsp;Minhan Song ,&nbsp;Tongyue Li ,&nbsp;Ying Zou ,&nbsp;Ruoyu Duan ,&nbsp;Zhimei Liu ,&nbsp;Suzhou Zhao ,&nbsp;Fang Fang","doi":"10.1016/j.ymgme.2025.109158","DOIUrl":"10.1016/j.ymgme.2025.109158","url":null,"abstract":"<div><h3>Objective</h3><div>To summarize clinical characteristics of the largest Chinese cohort of mitochondrial short-chain enoyl-CoA hydratase-1 deficiency (ECHS1D) and analyze the genotype-phenotype correlations.</div></div><div><h3>Methods</h3><div>This retrospective study enrolled 42 children with genetically diagnosed ECHS1D within the China Mitochondrial Disease Network. Patients were classified into severe infantile (SI), slowly progressive infantile (SPI), and late-onset phenotype (LP) based on onset age, disease progression rate, and gross motor impairment severity. Prognosis was assessed using the Modified Rankin Scale(mRS).</div></div><div><h3>Results</h3><div>Forty-two patients (25 male) were included, with a median onset age of 13.5 months (range 3–60). Paroxysmal dystonia (PD, 33.3 %) was the most common initial symptoms, followed by developmental delay(28.6 %) and regression(21.4 %). All patients had globus pallidus involvement and were diagnosed with Leigh syndrome (SI, <em>n</em> = 18; SPI, <em>n</em> = 13; LP, <em>n</em> = 11). SI cases all started with non-paroxysmal dystonia, and showed more frequent putamen (77.8 %) and caudate nucleus (72.2 %) involvement. In SPI and LP cases, PD was more common at onset, with milder symptoms and often isolated globus pallidus involvement. The proportions of elevated urinary metabolic markers 2,3-dihydroxy-2-methylbutyrate (2,3DH2MB) and S-(2-carboxypropyl) cysteamine (SCPCM) were 89.7 % and 93.1 % respectively, and the degree of their elevation was significantly correlated with phenotype severity. Regarding overall prognosis, 52.4 % of patients could walk independently (mRS &lt; 4), with three fatalities. SI cases had the worst prognosis, followed by SPI, while LP cases showed the best outcomes (<em>p</em> &lt; 0.05). In terms of genetics, all patients were compound heterozygous variants in the <em>ECHS1</em> gene, with 21 novel variants identified. The most common variant was the c.489G &gt; A (p.Pro163=) variant, which was found in 18 patients, accounting for as high as 42.8 % (allele frequency 0.214). And patients carrying this synonymous variant exhibited later onset age, longer diagnostic duration, milder phenotypes.</div></div><div><h3>Conclusions</h3><div>This study provides a comprehensive overview of ECHS1D, summarizing its clinical and genetic spectrum, and indicating that the c.489G &gt; A variant is a potential hotspot in the Chinese population. As findings from single-center studies may not be generalizable to a broader population, multi-center prospective studies are warranted.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109158"},"PeriodicalIF":3.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271536","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":"Doxecitine and doxribtimine treatment in an adult patient with thymidine kinase 2 deficiency","authors":"Elsbeth Chow ,&nbsp;Lindsey Miller ,&nbsp;Anna Clearman ,&nbsp;Patricia Arnold ,&nbsp;Mary Kay Koenig ,&nbsp;S. Nicholas Russo","doi":"10.1016/j.ymgme.2025.109159","DOIUrl":"10.1016/j.ymgme.2025.109159","url":null,"abstract":"<div><div>Thymidine kinase 2 (TK2) deficiency is an ultrarare mitochondrial depletion and deletion syndrome characterized by mutations in the nuclear <em>TK2</em> gene responsible for encoding the mitochondrial thymidine kinase 2 enzyme. TK2's role is to phosphorylate the nucleosides deoxycytidine (dC) and deoxythymidine (dT) required for mitochondrial DNA (mtDNA) replication; therefore, deficient TK2 enzymes result in dysfunctional replication of mtDNA. TK2 deficiency presents in children as progressive muscle weakness, respiratory difficulty, and mtDNA depletion. Fewer than 120 patients have been described in medical literature, and there are currently no FDA-approved treatments for TK2 deficiency. Provision of exogenous deoxynucleosides (dC/dT) allow for replication of mtDNA via cytosolic enzymes thymidine kinase 1 (TK1) and deoxycytidine kinase (dCK), as well as any residual TK2 activity. Here we describe a 26-year-old female with childhood-onset TK2 deficiency characterized by progressive myopathy, fatigue, weight loss, atrophy, bone fractures, dysphagia, neuropathy, and respiratory failure. With initiation of deoxynucleoside therapy and multiple therapy modalities (physical, occupational, and speech), her rate of decline slowed and she has shown steady improvement.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109159"},"PeriodicalIF":3.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271535","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":"C4OH-carnitine: an important marker of ketosis in patients with and without inborn errors of metabolism","authors":"Maria Laura Duque Lasio ,&nbsp;Maria Zaitsev ,&nbsp;Judith A. Hobert ,&nbsp;Irene De Biase ,&nbsp;Marzia Pasquali ,&nbsp;Tatiana Yuzyuk","doi":"10.1016/j.ymgme.2025.109160","DOIUrl":"10.1016/j.ymgme.2025.109160","url":null,"abstract":"<div><h3>Background</h3><div>Elevated C4OH (3-hydroxybutyryl−/3-hydroxyisobutyryl-) carnitine has been reported in physiologic ketosis, secondary to ketogenic diet, and is also observed in several Inborn Errors of Metabolism (IEMs). However, the reliability of plasma C4OH-carnitine as a marker of ketosis on routine acylcarnitine testing has not been extensively studied. The goal of this study was to correlate the plasma C4OH-carnitine levels with the measurements of plasma/serum β-hydroxybutyrate (BHB). We also investigated the prevalence of elevated C4OH-carnitine in different IEMs.</div></div><div><h3>Methods</h3><div>We conducted a retrospective analysis of &gt;75,000 samples sent to our laboratory for plasma acylcarnitine analysis. The concentrations of C4OH-carnitine and BHB were correlated in 559 samples with concurrent BHB and acylcarnitine profile (ACP). BHB was also directly measured in 151 samples submitted for acylcarnitine analysis. The range of C4OH-carnitine concentrations and the frequency of elevated C4OH-carnitine was evaluated in &gt;2000 samples from patients with known diagnosis of IEM.</div></div><div><h3>Results</h3><div>We observed a strong correlation between C4OH-carnitine and BHB concentration (Spearman coefficient <em>r</em> &gt; 0.80, <em>p</em> &lt; 0.0001). The overall concordance between C4OH-carnitine and BHB results in analyzed samples was 84 % with negative and positive predictive values of 74 % and 96 %, respectively. In the IEM cohort, isolated elevations of C4OH-carnitine were consistently present in a patient with L-3-hydroxyacyl-CoA dehydrogenase deficiency. A large number of samples from patients with beta-ketothiolase deficiency, methylmalonic acidemia (MMA) and propionic acidemia (PA) had high C4OH-carnitine (35 %, 21 % and 17 %, respectively) reflecting ketosis. Abnormal C4OH-carnitine was less commonly seen in multiple acyl-CoA dehydrogenase deficiency (7.7 %), very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, 5.8 %), glutaric acidemia type 1 (4.6 %), and medium-chain acyl-CoA dehydrogenase deficiency (0.4 %). Significantly higher concentrations of diagnostic acylcarnitine species were observed in MMA, PA and VLCADD samples with elevated C4OH-carnitine <em>vs</em> samples with normal C4OH-carnitine even after correcting for free carnitine.</div></div><div><h3>Conclusion</h3><div>Plasma C4OH-carnitine concentration showed a strong positive correlation with plasma/serum concentrations of BHB, demonstrating that elevated C4OH-carnitine is a reliable marker of ketosis. Elevated C4OH-carnitine in individuals with IEMs could indicate catabolic state and should prompt additional metabolic and nutritional evaluations to prevent metabolic decompensation.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109160"},"PeriodicalIF":3.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223324","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":"Fabry disease - a risk factor for renal cell cancer? - case series","authors":"Subadra Wanninayake ,&nbsp;L. van Dussen ,&nbsp;Antonio Ochoa-Ferraro ,&nbsp;Rupesh I Bhatt ,&nbsp;Charlotte Dawson ,&nbsp;Mirjam Langeveld ,&nbsp;Tarekegn Geberhiwot","doi":"10.1016/j.ymgme.2025.109157","DOIUrl":"10.1016/j.ymgme.2025.109157","url":null,"abstract":"<div><h3>Introduction</h3><div>Fabry disease (FD) is an X-linked lysosomal storage disease characterised by glycosphingolipid globotriaosylceramide (Gb3) accumulation in the lysosomes of multiple organs including the kidneys. Anecdotally we observed a higher-than-expected incidence of renal cell carcinoma (RCC) in FD patients.</div></div><div><h3>Methods</h3><div>Retrospective, observational study at two specialist national centres for lysosomal storage disorders (LSD) in the UK and Netherlands looking after a total of 520 patients with FD, 289 with a classical phenotype and 231 with non-classical ‘cardiac variant’ phenotype.</div></div><div><h3>Results</h3><div>There were 11/520 (equivalent 70.5/100000/year) incidences in 10 patients with an additional diagnosis of RCC. The median (IQR) age at RCC diagnosis was 55 (39–59) years. 5/10 were identified incidentally. RCC affected 6/289 (2.1 %) patients with classical Fabry disease and 5/231 (2.2 %) with the non-classical phenotype. The median (range) plasma lyso-Gb3 concentration was 21.6 (2.9–95.6 nmol/L). 55 % of RCCs were diagnosed before starting disease modifying treatment, the remaining were diagnosed 5–18 years after the start of treatment. Commonest subtype was clear-cell-RCC (7/11 incidences with 7 patients having WHO/ISUP grade 2 or above tumours. 3 had papillary-RCC (1 had two episodes at age 27 and 39).</div></div><div><h3>Conclusion</h3><div>The annual incidence of RCC in patients with FD was higher than the peak global incidence (70.5 vs 4.6/100000/year) and occurred at a younger age. FD may be an independent risk factor for RCC. This suggests that routine screening for RCC may be beneficial in patients with FD.</div><div><strong>Key learning points:</strong> Fabry disease may be an independent risk factor for renal cell carcinoma.</div><div><strong>What was known:</strong> Renal involvement, primarily progressive chronic kidney disease (CKD) is a well-known manifestation of Fabry disease.</div><div><strong>This study adds:</strong> Our findings indicate a significant increase in RCC among patients with FD.</div><div><strong>Potential impact:</strong> Effective screening tool will be available for patient with this genetic condition and further research into the mechanisms by which GLA gene variants increase RCC risk may enhance our understanding of RCC pathophysiology and inform the development of new therapeutic approaches.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109157"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144229647","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":"Cover 2 / Ed. Board","authors":"","doi":"10.1016/S1096-7192(25)00133-7","DOIUrl":"10.1016/S1096-7192(25)00133-7","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 2","pages":"Article 109142"},"PeriodicalIF":3.7,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144139564","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":"Beyond proline shortage: New insights into the pathophysiology of prolidase deficiency","authors":"S.G. Sainsbury ,&nbsp;T. van den Broek ,&nbsp;P.M. van Hasselt","doi":"10.1016/j.ymgme.2025.109152","DOIUrl":"10.1016/j.ymgme.2025.109152","url":null,"abstract":"<div><div>Prolidase deficiency is an ultra-rare metabolic disorder caused by pathogenic variants in the <em>PEPD</em> gene, which causes a wide range of symptoms including chronic ulcers, recurrent infections, systemic lupus erythematosus (SLE), facial dysmorphisms and developmental delay. How decreased prolidase activity - thus an inability to cleave C-terminal proline imidodipeptides - eventually causes these symptoms is as yet poorly understood. However, recent research has unveiled additional roles of prolidase in cellular homeostasis, including regulation of important signalling molecules such as TGF-β, VEGF and p53. This study proposes that dysregulation of these pathways leads to impairments in important wound healing processes, which could explain the combination of chronic ulcers, developmental delay and propensity for autoimmunity, with symptoms such as bone deformities and recurrent infections being the result of impaired intracellular signalling. This article provides a more comprehensive understanding of prolidase deficiency and opens the way for developing new therapeutic avenues.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109152"},"PeriodicalIF":3.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166988","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":"Enzyme replacement therapy using a modified α-N-acetylgalactosaminidase to suppress progressive glycolipid accumulation and escape from antidrug antibody formation in young human NAGA-transgenic/Gla-knockout mice","authors":"Hitoshi Sakuraba ,&nbsp;Takahiro Tsukimura ,&nbsp;Tomoko Shiga ,&nbsp;Seiji Saito ,&nbsp;Youichi Tajima ,&nbsp;Ikuo Kawashima ,&nbsp;Tomoko Fukushige ,&nbsp;Tadayasu Togawa","doi":"10.1016/j.ymgme.2025.109151","DOIUrl":"10.1016/j.ymgme.2025.109151","url":null,"abstract":"<div><div>Enzyme replacement therapy (ERT) using recombinant human α-galactosidase A (AGAL) is a standard therapy for Fabry disease. However, systemic reviews have reported that recurrent injection of the enzyme can induce the formation of harmful antidrug antibodies (ADAs) in male patients with Fabry disease. Unfortunately, to date no recommended ERT drugs facilitating escape from ADA formation have yet been established. Accordingly, we focused on α-<em>N</em>-acetylgalactosaminidase (NAGA), which has a protein structure that is similar to that of AGAL. Previously, we had prepared a modified NAGA (<em>p. S188E</em> and <em>p. A191L</em>) and determined the biochemical properties of the new enzyme. In this study we verified the efficacy of the modified NAGA, both in silico and via cell and animal experiments. The molecular dynamics simulation results suggested that the enzyme has an affinity for α-D-galactose (α-Gal) as a ligand. Moreover, these results also suggested that the modified NAGA may hydrolyze the terminal α-Gal moieties of glycoconjugates. The cell experiments revealed that the modified NAGA incorporated into cultured Fabry fibroblasts was more stable than recombinant human AGAL, despite the specific enzyme activity of the former being lower than that of the latter. Additional animal experiments revealed that human <em>NAGA</em>-transgenic/<em>Gla</em>-knockout mice were tolerant of recurrent administration of the modified NAGA, and that the modified NAGA notably did not induce the formation of ADAs. Moreover, the enzyme also suppressed the progressive accumulation of globotriaosylceramide and globotriaosylsphingosine in organs/tissues, thereby improving morphological changes in young mice. Overall, these findings suggest that the modified NAGA is a promising ERT drug candidate for patients with Fabry disease, especially for those who are likely to produce anti-AGAL antibodies.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109151"},"PeriodicalIF":3.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166939","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":"Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form","authors":"Sarah Clifford ,&nbsp;Renae J. Stefanetti ,&nbsp;Roxana Bahar ,&nbsp;Magnus J. Hansson ,&nbsp;Gráinne S. Gorman ,&nbsp;Amel Karaa","doi":"10.1016/j.ymgme.2025.109153","DOIUrl":"10.1016/j.ymgme.2025.109153","url":null,"abstract":"<div><h3>Background</h3><div>Fatigue is a debilitating symptom in patients with primary mitochondrial disease nPMD). Developing new treatments that improve fatigue is a patient priority but is hampered by a lack of fit-for-purpose patient-reported outcome measures (PROMs). We aimed to understand the impact of fatigue on the lives of people with PMD and develop a brief PMD-specific PROM to evaluate fatigue in clinical trials.</div></div><div><h3>Methods</h3><div>Adults with genetically confirmed PMD and self-reported moderate-to-severe fatigue and myopathy/exercise intolerance participated in a concept elicitation interview to explore their experiences of fatigue. Interview transcripts were coded thematically using MAXQDA™. Characteristics and impacts that emerged from the interviews were mapped to items in the PROMIS® Fatigue item bank. Participants then engaged in a cognitive interview to assess relevance and understandability of PROMIS Fatigue items considered for the PROM.</div></div><div><h3>Results</h3><div>Twelve adults with PMD (<em>n</em> = 8 women, age 20–75 years) were interviewed. The most frequently reported characteristics of fatigue included tiredness, muscle weakness/fatigue, exhaustion, lack of energy, and mental fatigue. Fatigue affected patients' ability to perform daily life activities, including household chores, leisure activities, physical activity/exercise, and work/school, and negatively affected mood and relationships. Nine items were included in the final PROM based on level of endorsement of underlying concepts elicited by the concept elicitation interviews and relevance, clarity, and ease of answering, as assessed in the cognitive interviews.</div></div><div><h3>Conclusion</h3><div>The nine-item PROMIS Fatigue Mitochondrial Disease Short Form is the first PROM designed specifically to assess fatigue in PMD. This study demonstrates the content validity of the short form, and future longitudinal studies will assess its psychometric properties.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 4","pages":"Article 109153"},"PeriodicalIF":3.7,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144189673","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":"Missense mutations in MMACHC protein from cblC disease affect its conformational stability and vitamin B12-binding activity: The example of R161Q mutation","authors":"Lisa Longo ,&nbsp;Loredana Randazzo ,&nbsp;Michela Bollati ,&nbsp;Rita Carrotta ,&nbsp;Maria Assunta Costa ,&nbsp;Matteo De Rosa ,&nbsp;Maria Rosalia Mangione ,&nbsp;Vincenzo Martorana ,&nbsp;Giulia Culletta ,&nbsp;Marco Tutone ,&nbsp;Eleonora Mari ,&nbsp;Maria Grazia Ortore ,&nbsp;Paula M. Garcia-Franco ,&nbsp;Adrian Velazquez-Campoy ,&nbsp;Rosa Passantino ,&nbsp;Silvia Vilasi","doi":"10.1016/j.ymgme.2025.109150","DOIUrl":"10.1016/j.ymgme.2025.109150","url":null,"abstract":"<div><div>MMACHC protein plays a crucial role in the metabolism of vitamin B12 (cobalamin, Cbl) by catalyzing its conversion into the active forms adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which serve as essential cofactors in key cellular reactions. Mutations in the gene encoding MMACHC lead to the rare metabolic disorder known as methylmalonic aciduria and homocystinuria, cblC type. This condition predominantly affects children and is characterized by cardiovascular dysfunction, intellectual disability, and a severe form of maculopathy. The most common missense mutation, R161Q, impairs enzymatic activity despite not being directly involved in cobalamin binding. Here, using a comprehensive set of biophysical techniques, we demonstrate that this pathogenic variant compromises MMACHC structural stability, alters the thermal unfolding cooperativity and pathway, as well as the populations of conformational intermediates. Moreover, we show that the R161Q mutation decreases AdoCbl binding affinity and impairs the protein's ability to form homodimers, which are supposed to have a functional role. A partial recovery in protein activity upon treatment with betaine, an osmolyte known for its stabilizing effect on proteins, was observed. This suggests a direct correlation between the energetics of MMACHC thermal unfolding and its functional activity. These findings contribute to a deeper understanding of the molecular mechanisms underlying MMACHC function and open avenues for potential therapeutic interventions.</div></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":"145 3","pages":"Article 109150"},"PeriodicalIF":3.7,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147861","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}