Molecular genetics and metabolism最新文献

{"title":"Developing a scoring system for gene curation prioritization in lysosomal diseases","authors":"","doi":"10.1016/j.ymgme.2024.108572","DOIUrl":"10.1016/j.ymgme.2024.108572","url":null,"abstract":"<div><h3>Introduction</h3><p>Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels.</p></div><div><h3>Methods</h3><p>Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into “Overall Definition,” “Phenotype,” and “Pathophysiology.” These criteria included concepts such as the “accumulation of undigested or partially digested macromolecules within the lysosome” and being “associated with a wide spectrum of clinical manifestations impacting multiple organs and systems.” The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between “major” and “minor” criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List.</p></div><div><h3>Results</h3><p>The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (<em>GRN, SLC29A3, CLN7</em> and <em>VPS33A</em>) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as <em>MTOR</em>, <em>OCRL</em>, and <em>SLC9A6</em>, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panel","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168557","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":"Treatment of congenital disorders of glycosylation: An overview","authors":"","doi":"10.1016/j.ymgme.2024.108567","DOIUrl":"10.1016/j.ymgme.2024.108567","url":null,"abstract":"<div><p>While the identification and diagnosis of congenital disorders of glycosylation (CDG) have rapidly progressed, the available treatment options are still quite limited. Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause. However, recent years have brought about remarkable advances in treatment approaches for some CDG. Innovative therapies, targeting both the root cause and resulting manifestations, have transitioned from the research stage to practical application. The present paper aims to provide a detailed overview of these exciting developments and the rising concepts that are used to treat these ultra-rare diseases.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004517/pdfft?md5=11fe9626a95e4fd00999824a20760034&pid=1-s2.0-S1096719224004517-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137123","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":"Assessing carnosinase 1 activity for diagnosing congenital disorders of glycosylation","authors":"","doi":"10.1016/j.ymgme.2024.108571","DOIUrl":"10.1016/j.ymgme.2024.108571","url":null,"abstract":"<div><p>Diagnosing Congenital Disorders of Glycosylation (CDG) is challenging due to clinical heterogeneity and the limited sensitivity of the classic serum transferrin isoelectric focusing (IEF) or capillary zone electrophoresis test. This study investigates the potential of using the glycoprotein carnosinase 1 (CN1) activity as a diagnostic marker for CDG patients. CN1 activity was measured photometrically in serum from 81 genetically confirmed CDG patients and healthy individuals. While the IEF transferrin method detected 77 patients, four remained undetected.</p><p>In healthy individuals, serum CN1 activity ranged from 0.1 to 6.4 μmol/ml/h depending on age, with mean CN1 activities up to four-fold higher than in CDG patients. CDG patients´ CN1 activities never exceeded 2,04 μmol/ml/h. Using the 25th percentile to differentiate between groups, the test performance varied by age. For children over 10 years old, the sensitivity and specificity were 96 % and 83 %, respectively. For those under 10, sensitivity and specificity dropped to 71 % and to 64 %. However, CN1 activity successfully identified three of four patients with normal IEF patterns.</p><p>Although mean CN1 activity in CDG patients is significantly lower than in healthy controls, the test's reliability for classic CDG diagnosis is limited, as the diagnosis is usually made at a young age. Nevertheless, it is a simple, cost-effective assay that can complement classic tests, especially in settings with limited access to complex methods or for patients with normal transferrin patterns but suspicious for CDG.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004554/pdfft?md5=7d0d0abfac617b127769b9b702d30650&pid=1-s2.0-S1096719224004554-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126214","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":"Continuous glucose monitoring metrics in people with liver glycogen storage disease and idiopathic ketotic hypoglycemia: A single-center, retrospective, observational study","authors":"","doi":"10.1016/j.ymgme.2024.108573","DOIUrl":"10.1016/j.ymgme.2024.108573","url":null,"abstract":"<div><h3>Background</h3><p>Cohort data on continuous glucose monitoring (CGM) metrics are scarce for liver glycogen storage diseases (GSDs) and idiopathic ketotic hypoglycemia (IKH). The aim of this study was to retrospectively describe CGM metrics for people with liver GSDs and IKH.</p></div><div><h3>Patients and methods</h3><p>CGM metrics (descriptive, glycemic variation and glycemic control parameters) were calculated for 47 liver GSD and 14 IKH patients, categorized in cohorts by disease subtype, age and treatment status, and compared to published age-matched CGM metrics from healthy individuals. Glycemic control was assessed as time-in-range (TIR; ≥3.9 - ≤7.8 and ≥3.9 - ≤10.0 mmol/L), time-below-range (TBR; &lt;3.0 mmol/L and ≥3.0 - ≤3.9 mmol/L), and time-above-range (TAR; &gt;7.8 and &gt;10.0 mmol/L).</p></div><div><h3>Results</h3><p>Despite all patients receiving dietary treatment, GSD cohorts displayed significantly different CGM metrics compared to healthy individuals. Decreased TIR together with increased TAR were noted in GSD I, GSD III, and GSD XI (Fanconi-Bickel syndrome) cohorts (all <em>p</em> &lt; 0.05). In addition, all GSD I cohorts showed increased TBR (all <em>p</em> &lt; 0.05). In GSD IV an increased TBR (p &lt; 0.05) and decreased TAR were noted (p &lt; 0.05). In GSD IX only increased TAR was observed (p &lt; 0.05). IKH patient cohorts, both with and without treatment, presented CGM metrics similar to healthy individuals.</p></div><div><h3>Conclusion</h3><p>Despite dietary treatment, most liver GSD cohorts do not achieve CGM metrics comparable to healthy individuals. International recommendations on the use of CGM and clinical targets for CGM metrics in liver GSD patients are warranted, both for patient care and clinical trials.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004578/pdfft?md5=4652934eedba1477b5d1d0c1f830c15e&pid=1-s2.0-S1096719224004578-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145989","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":"Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders","authors":"","doi":"10.1016/j.ymgme.2024.108566","DOIUrl":"10.1016/j.ymgme.2024.108566","url":null,"abstract":"<div><h3>Objective</h3><p>In individuals with urea cycle disorders (UCDs) and neonatal disease onset, extracorporeal detoxification by continuous kidney replacement therapy is considered the therapeutic method of choice in addition to metabolic emergency treatment to resolve hyperammonemic decompensation. However, the indications for the initiation of dialysis are heterogeneously implemented transnationally, thereby hampering our understanding of (optimal) short-term health outcomes.</p></div><div><h3>Methods</h3><p>We performed a retrospective comparative analysis evaluating the therapeutic effects of initial dialysis on survival as well as neurocognitive outcome parameters in individuals with UCDs in comparison to a severity-adjusted non-dialyzed control cohort. Overall, 108 individuals with a severe phenotype of male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) were investigated by stratification based on a recently established and validated genotype-specific disease prediction model.</p></div><div><h3>Results</h3><p>Mortality is associated with the height of initial peak plasma ammonium concentration, but appears to be independent from treatment with initial dialysis in mOTC-D. However, improved survival after initial dialysis was observed in CTLN1, while there was a trend towards improved survival in ASA. In survivors, annual frequency of (subsequent) metabolic decompensations did not differ between the dialyzed and non-dialyzed cohorts. Moreover, treatment with initial dialysis was not associated with improved neurocognitive outcomes.</p></div><div><h3>Interpretation</h3><p>The present severity-adjusted comparative analysis reveals that general practice of initial dialysis is neither associated with improved survival in individuals with mOTC-D nor does it differ with regard to the neurocognitive outcome for the investigated UCD subtypes. However, initial dialysis might potentially prove beneficial for survival in CTLN1 and ASA.</p><p><strong>Clinical trial registration</strong>: The UCDC database is recorded at the US National Library of Medicine (<span><span>https://clinicaltrials.gov</span><svg><path></path></svg></span>).</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004505/pdfft?md5=95d6eb8d68af172011e052eabd55c6b2&pid=1-s2.0-S1096719224004505-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240409","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":"Maple syrup urine disease diagnosis in Brazilian patients by massive parallel sequencing","authors":"","doi":"10.1016/j.ymgme.2024.108569","DOIUrl":"10.1016/j.ymgme.2024.108569","url":null,"abstract":"<div><p>Biallelic pathogenic variants cause maple syrup urine disease (MSUD) in one of the branched-chain α-keto acid dehydrogenase (BCKDH) complex genes (<em>BCKDHA</em>, <em>BCKDHB</em>, <em>DBT</em>, <em>DLD</em>, and <em>PPM1K</em>) leading to the accumulation of leucine, isoleucine, and valine. This study aimed to perform a molecular diagnosis of Brazilian patients with MSUD using gene panels and massive parallel sequencing. Eighteen Brazilian patients with a biochemical diagnosis of MSUD were analyzed by massive parallel sequencing in the Ion PGM Torrent Server using a gene panel with the <em>BCKDHA</em>, <em>BCKDHB</em>, and <em>DBT</em> genes. The American College of Medical Genetics and Genomics guidelines were used to determine variant pathogenicity. Thirteen patients had both variants found by massive parallel sequencing, whereas 3 patients had only one variant found. In 2 patients, the variants were not found by this analysis. These 5 patients required additional Sanger sequencing to confirm their genotype. Twenty-five pathogenic variants were identified in the 3 MSUD-related genes (<em>BCKDHA</em>, <em>BCKDHB</em>, and <em>DBT</em>). Most variants were present in the <em>BCKDHB</em> gene, and no common variants were found. Nine novel variants were observed: c.922 A &gt; G, c.964C &gt; A, and c.1237 T &gt; C in the <em>BCKDHA</em> gene; and c.80_90dup, c.384delA, c.478 A &gt; T, c.528C &gt; G, c.977 T &gt; C, and c.1039-2 A &gt; G in the <em>BCKDHB</em> gene. All novel variants were classified as pathogenic. Molecular modeling of the novel variants indicated that the binding of monomers was affected in the BCKDH complex tetramer, which could lead to a change in the stability and activity of the enzyme. Massive parallel sequencing with targeted gene panels seems to be a cost-effective method that can provide a molecular diagnosis of MSUD.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142168556","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":"CIC variants and folinic acid-responsive seizures","authors":"","doi":"10.1016/j.ymgme.2024.108574","DOIUrl":"10.1016/j.ymgme.2024.108574","url":null,"abstract":"","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142137124","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":"Sensitivity of transferrin isoform analysis for PMM2-CDG","authors":"","doi":"10.1016/j.ymgme.2024.108564","DOIUrl":"10.1016/j.ymgme.2024.108564","url":null,"abstract":"<div><p>Transferrin isoform analysis is an established laboratory test for congenital disorders of glycosylation (CDG). Despite its long history of clinical use, little has been published about its empirical sensitivity for specific conditions. We conducted a retrospective analysis of ten years of testing data and report our experience with transferrin testing for type I profiles and its sensitivity for the most common congenital disorder of glycosylation, PMM2-CDG. The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly demonstrate two known, recurrent variants enriched in false positive cases highlighting an important limitation of the test. The data confirm the clinical validity of transferrin isotype analysis as a screening test for disorders of protein N-linked glycosylation and as functional test for <em>PMM2</em> genotypes of uncertain significance.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004487/pdfft?md5=488429242a92f1e3b46725149e4da88c&pid=1-s2.0-S1096719224004487-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142098970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a signs and symptoms outcome measure for caregivers of patients with methylmalonic acidemia and propionic acidemia (MMAPAQ)","authors":"","doi":"10.1016/j.ymgme.2024.108577","DOIUrl":"10.1016/j.ymgme.2024.108577","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background and objective&lt;/h3&gt;&lt;p&gt;Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare inborn errors of metabolism with shared signs and symptoms that are associated with significant morbidity and mortality. No disease-specific clinical outcomes assessment instruments for MMA and/or PA currently exist to capture the patient perspective in clinical trials. Because patients with these conditions are generally young and have cognitive impairments, an observer-reported outcome (ObsRO) instrument is crucial. We report results from qualitative research supporting development of the Methylmalonic Acidemia and Propionic Acidemia Questionnaire (MMAPAQ), a signs and symptoms ObsRO measure for caregivers of patients with MMA and/or PA.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Concept elicitation (CE) interviews were conducted with 35 participants across 2 studies who were aged ≥18 years and caregivers of patients with a confirmed diagnosis of MMA or PA, and an additional 5 patients aged ≥6 years with MMA or PA in Study 1, to identify core signs/symptoms for inclusion in the MMAPAQ. All interviews were conducted in English. Study 2 included cognitive interviews (CI) with caregivers and clinical experts to further assess content validity. CE and a conceptual framework review were also conducted with clinical experts to further support findings.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;A consistent set of signs/symptoms of MMA and PA were reported by eligible caregivers interviewed in study 1 (&lt;em&gt;n&lt;/em&gt; = 21) and study 2 (&lt;em&gt;n&lt;/em&gt; = 14), representing 11 patients with MMA and 20 with PA. Based on concepts reported in study 1, a draft instrument was constructed and compared with the Pediatric Quality of Life Inventory™ (PedsQL™) and Family Impact module, demonstrating face validity for measuring key signs/symptoms important to patients and caregivers. The PedsQL™ and Family Impact modules were preferred to assess patient and caregiver impacts. Two waves of CE and CIs were conducted in study 2, with wave 1 resulting in removal of 7 items and other revisions to improve clarity, and wave 2 resulting in modification of examples used for 2 items. The final instrument consisted of the following 7 items assessed over the past 7 days using a Likert-type response scale ranging from “never” to “very often”: uncontrollable or involuntary movements, dehydration, rapid breathing at rest, appearing lethargic, appearing disinterested in eating, refusing to eat, and vomiting.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;This study establishes the content validity of the MMAPAQ as the first ObsRO questionnaire for measuring core signs and symptoms of MMA and PA in clinical trials and community research. Scoring and psychometric measurement properties of the MMAPAQ will be established in future studies. The PedsQL™ was found to have face validity in measuring concepts that affect the MMA and PA patient populations and should also be considered for use in clinical trials in MMA and","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S109671922400461X/pdfft?md5=2f6d364f0bed4c7573b3801b3060eed7&pid=1-s2.0-S109671922400461X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142240410","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":"Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model","authors":"","doi":"10.1016/j.ymgme.2024.108575","DOIUrl":"10.1016/j.ymgme.2024.108575","url":null,"abstract":"<div><p>Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in <em>ALMS1</em> have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of <em>ALMS1</em> is unknown, particularly in a cardiovascular context. To understand the role of <em>ALMS1</em> in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which <em>ALMS1</em> was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that <em>ALMS1</em> knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed <em>ALMS1</em> knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with <em>ALMS1</em> knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated β-galactosidase (SA-β gal) staining assay, we identified increased senescence of <em>ALMS1</em> knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of <em>ALMS1</em> in infantile cardiomyopathy in AS, using iPSC-CMs as a ‘disease in a dish’ model to provide insights into multiple aspects of this complex disease.</p></div>","PeriodicalId":18937,"journal":{"name":"Molecular genetics and metabolism","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1096719224004591/pdfft?md5=73579819ff6ee142177ea42d49285583&pid=1-s2.0-S1096719224004591-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145988","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}