Human Mutation最新文献

{"title":"A Novel Missense Variant of BMPR1A in Juvenile Polyposis Syndrome: Assessment of Structural and Functional Alternations","authors":"Mengyuan Yang,&nbsp;Ziyan Tong,&nbsp;Zhijun Yuan,&nbsp;Bingjing Jiang,&nbsp;Yingxin Zhao,&nbsp;Dong Xu,&nbsp;Ying Yuan","doi":"10.1155/humu/7317429","DOIUrl":"https://doi.org/10.1155/humu/7317429","url":null,"abstract":"<p>Juvenile polyposis syndrome (JPS) is a rare precancerous condition associated with a high susceptibility to colorectal cancer. The genetic basis of JPS has been reported to lie in germline mutations in BMPR1A or SMAD4, resulting in diverse clinical manifestations and an elusive underlying mechanism. We firstly utilized a 139-gene next-generation sequencing (NGS) panel to detect the germline variants and further employed various prediction tools to assess the pathogenicity and functional alternations. Consequently, we identified a novel pathogenic BMPR1A missense variant (c.355C&gt;T; p.R119C). More importantly, we proposed for the first time that the missense variant would lead to a decrease in molecular weight, potentially associated with reduced protein stability, diminished posttranslational modifications, and aberrant alternative splicing. These findings may provide novel perspectives for further exploration into the role of BMPR1A in JPS development. Also, we hope to encourage clinicians to underscore the importance of genetic testing and analysis in facilitating the diagnosis and treatment of diseases.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7317429","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Occurrence of a Missense Variant (c.471C>A) in the FGF23 Gene Related to Hyperostosis–Hyperphosphatemia Syndrome With a Possible Founder Effect","authors":"Maryam Sedghi,&nbsp;Elika Esmaeilzadeh Gharehdaghi,&nbsp;Vahid Ziaee,&nbsp;Farzaneh Abbasi,&nbsp;Hamid Reza Aghaei Meybodi,&nbsp;Elina Smailey,&nbsp;Mehrzad Mehdizadeh,&nbsp;Seyyed Reza Raeeskarami,&nbsp;Nahid Aslani,&nbsp;Sahar Naderi Shiran,&nbsp;Mehdi Vafadar,&nbsp;Mahsa M. Amoli","doi":"10.1155/humu/6382674","DOIUrl":"https://doi.org/10.1155/humu/6382674","url":null,"abstract":"<p><b>Background:</b> The autosomal recessive metabolic disorder hyperostosis–hyperphosphatemia syndrome (HHS) is characterized by hyperphosphatemia, hyperostosis, and recurrent bone lesions. Patients may develop ectopic and vascular calcification and may present diaphyseal pain of the long bones that is misdiagnosed as osteomyelitis. Mutations in <i>GALNT3</i> and <i>FGF23</i> genes were detected in patients with HHS. The main manifestations of these patients are increased levels of phosphate reabsorption from kidneys and painful swelling of long bones alongside with normal levels of vitamin D and parathormone.</p><p><b>Method:</b> We performed whole-exome sequencing (WES) in seven Iranian patients. These patients were referred from several specialist clinics. Seven irrelevant families were examined for genetic mutations.</p><p><b>Results:</b> WES revealed the deleterious missense mutation c.471C&gt;A, p. F157L in all affected members of six families. The variant c.1524+1G&gt;A in the <i>GALNT3</i> gene was found in the remaining patient which is reported previously. These variants were confirmed utilizing segregation studies in the pedigrees.</p><p><b>Conclusion:</b> Our data together with previous studies related to mutations in <i>FGF23</i> in Iran strongly support that p. F157L mutation is abundantly prevalent in patients with Iranian origin and is likely to be a founder mutation; however, it requires further confirmative study. The result of this study suggests that p. F157L mutation should be investigated at the first step in genetic analysis of patients with HHS. This enables fast and accurate focused molecular diagnosis and would be effective for use in carrier screening as well as in prenatal diagnosis (PND) and preimplantation genetic diagnosis (PGD).</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6382674","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and Functional Characterization of a Novel PRPS1 Variant in X-Linked Nonsyndromic Hearing Loss: Insights From Zebrafish and Cellular Models","authors":"Yining Wan,&nbsp;Jinqiu Li,&nbsp;Yingyuan Guo,&nbsp;Fang Guo,&nbsp;Ying Zhao,&nbsp;Yue Li,&nbsp;Xia Yang,&nbsp;Huidan Chen,&nbsp;Shimin Xie,&nbsp;Mingyong Wang,&nbsp;Guofang Guan,&nbsp;Yilong Zhu,&nbsp;Xiao Li","doi":"10.1155/humu/6690588","DOIUrl":"https://doi.org/10.1155/humu/6690588","url":null,"abstract":"<p><b>Purpose:</b> The study was aimed at identifying the pathogenic gene responsible for X-linked nonsyndromic hearing loss (NSHL) in a five-generation Chinese family and at elucidating the gene’s function both in vivo using a zebrafish model and in vitro using PRPS1 knockdown HEI-OC1 cells.</p><p><b>Methods:</b> Exome sequencing (ES) and Sanger sequencing were used to identify the pathogenic variants. A transgenic zebrafish model overexpressing the novel PRPS1 variant (c.494G&gt;A: p.Cys165Tyr) was constructed, and PRPS1 was knocked down in HEI-OC1 cells using siRNA to explore the underlying mechanisms. Hair cell development and behavior were assessed in zebrafish, and mitochondrial function and cell viability were analyzed in HEI-OC1 cells.</p><p><b>Results:</b> A novel missense variant (c.494G&gt;A: p.Cys165Tyr) in the PRPS1 gene was identified as the pathogenic variant causing progressive X-linked deafness-1 (DFNX1). The variant led to hair cell death in zebrafish, with disrupted swimming behavior. In HEI-OC1 cells, PRPS1 knockdown resulted in downregulation of the nicotinamide adenine dinucleotide (NAD⁺)/sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) pathway, increased reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and apoptosis, which were partially rescued by pretreatment with nicotinamide mononucleotide (NMN), a precursor of NAD⁺.</p><p><b>Conclusion:</b> The study reports a novel PRPS1 variant contributing to the variant spectrum of PRPS1 and highlights the role of PRPS1 deficiency in increasing oxidative stress-induced hair cell apoptosis via the NAD⁺/SIRT3/SOD2 pathway. These findings provide new insights into the molecular mechanisms of PRPS1-related hearing loss and potential therapeutic targets.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6690588","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo ACTB Variant Associated With Juvenile-Onset Temporal Lobe Epilepsy With Favorable Outcomes","authors":"Hong-Jun Yan,&nbsp;Peng-Yu Wang,&nbsp;Wen-Hui Liu,&nbsp;Yu-Jie Gu,&nbsp;Jia-Cheng Pan,&nbsp;Hua Li,&nbsp;Sheng Luo","doi":"10.1155/humu/9951922","DOIUrl":"https://doi.org/10.1155/humu/9951922","url":null,"abstract":"<p>Genetic factors are estimated to contribute to 80% of people with epilepsy. However, only four genes were reported to be associated with temporal lobe epilepsy (TLE). This study is aimed at investigating the association between <i>ACTB</i> and TLE. Trio-based exome sequencing was performed in a patient, and a de novo <i>ACTB</i> variant was identified. The patient presented with TLE featuring by age of onset in juvenile, seizure-free status in adulthood, complications of memory decline and irritability, epileptic discharges in the bilateral temporal lobes, and bilateral hippocampal sclerosis. The pathogenicity of the identified <i>ACTB</i> variant was supposed by multiple pieces of evidence, including the missense tolerance ratio of 0%, high conservation of the affected residue, predicted to be “damaging” or “conserved” by 17 in silico tools, and classification of likely pathogenic variant by the American College of Medical Genetics and Genomics (ACMG) guidelines. Protein modeling indicated the alteration of protein structure and stability caused by the identified variant. The spatiotemporal expression of <i>ACTB</i> is consistent with the phenotypic features of this patient. This study suggested that <i>ACTB</i> is a novel candidate causative gene of TLE. The correlation between phenotypes and spatial–temporal expression provides a novel perspective for further exploration of the pathogenesis and prognosis of the disease.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9951922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel USH2A Mutations in a Consanguineous Chinese Family With Usher Syndrome","authors":"Haolin Wang,&nbsp;Bo Wei,&nbsp;Jiaxin Guo,&nbsp;Xiawei Wu,&nbsp;Tongdan Zou,&nbsp;Ting Wang,&nbsp;Tiantian Zhang,&nbsp;Bo Gong,&nbsp;Jilong Hao,&nbsp;Houbin Zhang,&nbsp;Le Wang","doi":"10.1155/humu/6391770","DOIUrl":"https://doi.org/10.1155/humu/6391770","url":null,"abstract":"<p>Usher syndrome (USH) is a rare genetic disease characterized by sensorineural deafness and blindness called retinitis pigmentosa, and it is inherited in an autosomal recessive pattern with a prevalence of four to 17 per 100,000 people worldwide. In this study, a consanguineous Chinese family with USH, including two affected individuals and five unaffected individuals, was recruited. All subjects received an ophthalmic examination and an auditory examination. The two USH patients exhibited severe early-onset hearing and vision loss. DNA samples from the two USH patients were analyzed using whole-exome sequencing. A novel homozygous frameshift mutation (NM_206933.4:c.6379_6380delinsC, p.G2127Pfs∗25) in <i>USH2A</i>, resulting in a truncated <i>USH2A</i> protein lacking 3051 amino acids, was identified in the proband. In addition, novel compound mutations in <i>USH2A</i> (one allele harboring NM_206933.4:c.9958G&gt;T, p.G3320C; NM_206933.4:c.8284C&gt;G, p.P2762A; and the other NM_206933.4:c.6379_6380delinsC; p.G2127Pfs∗25) were identified in the other affected individual. In silico analysis predicts that while the p.G3320C mutation has little impact on the local structure around the mutation site, the p.P2762A substitution may alter the protein’s interaction with its binding partners. In addition, p.G2127Pfs∗25 causes a truncation of a major portion of the protein that severely disrupts the protein structure and results in the loss of its function. In conclusion, this study identified novel USH mutations in <i>USH2A</i> and expanded the spectrum of disease-associated variants in the <i>USH2A</i> gene, which will promote the molecular screening of genetic mutations in USH patients.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6391770","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinic Examination and Gene Diagnosis for a Birt–Hogg–Dubé Syndrome Family With a Novel flcn Frameshift Mutation Causing Nonsense-Mediated mRNA Degradation","authors":"Yang Xu,&nbsp;Jie Gao,&nbsp;Yang An,&nbsp;Chenxi Zou,&nbsp;Guoqing Ding,&nbsp;Guohua Yang","doi":"10.1155/humu/7194418","DOIUrl":"https://doi.org/10.1155/humu/7194418","url":null,"abstract":"<p><b>Background:</b> Birt–Hogg–Dubé syndrome (BHD) was an autosomal dominant disorder caused by a mutation in the folliculin (<i>FLCN</i>) gene and characterized by benign cutaneous fibrofolliculomas in the head and neck, pulmonary cysts, spontaneous pneumothorax, and combined renal tumors.</p><p><b>Methods:</b> This study reported a familial case presenting multiple pulmonary bullae, recurrent spontaneous pneumothorax, diffuse cystic lesions in both lungs, and renal cysts. To further clarify the diagnosis, next-generation sequencing (NGS) was performed in conjunction with the clinical diagnostic criteria for Birt–Hogg–Dubé. The eukaryotic recombinant expression vectors of pEGFP-C1-<i>FLCN</i> and knock-in <i>FLCN</i> mutation by CRISPR/Cas9 were conducted in 293 T and BEAS-2B cell lines. The mRNA and protein expression of the <i>FLCN</i> mutation were verified by fluorescence quantitative PCR and Western blot assay. Nonsense-mediated mRNA decay (NMD) assays and immunohistochemical assays were conducted to elucidate the pathogenicity of the mutation and explore potential mechanisms.</p><p><b>Results:</b> A unique, novel, unspecified significance <i>FLCN</i> mutation NM_144997.7: c.21_22del (p. Cys8 Profs ^∗28) in Exon 4 was detected in both patients. The results demonstrated that the newly identified <i>FLCN</i> frameshift mutation significantly decreased <i>FLCN</i> mRNA and protein expression. The NMD complex recognized and degraded mRNAs containing a premature termination codon (PTC) in the open reading frame of the <i>FLCN</i> frameshift mutation, resulting in haploinsufficiency and ultimately contributing to the manifestation of BHD. Protein expression on the AMP-activated protein kinase (AMPK), Wnt/<i>β</i>-catenin, and mammalian target of rapamycin (mTOR) signaling pathways by immunohistochemistry indicated that <i>FLCN</i> frameshift mutations were responsible for BHD through the activation of AMPK, Wnt/<i>β</i>-catenin, and mTOR signaling pathways.</p><p><b>Conclusion:</b> The study demonstrated that a novel <i>FLCN</i> frameshift mutation was responsible for the pathogenesis of BHD and preliminarily demonstrated that <i>FLCN</i> causes BHD through the AMPK, Wnt/<i>β</i>-catenin, and mTOR signaling pathways.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7194418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporating Nanopore Sequencing Into a Diverse Diagnostic Toolkit for Incontinentia Pigmenti","authors":"Simone Ahting,&nbsp;Denny Popp,&nbsp;Henry Oppermann,&nbsp;Vincent Strehlow,&nbsp;Maria Fasshauer,&nbsp;Bernt Popp,&nbsp;Maike Karnstedt,&nbsp;Isabell Schumann","doi":"10.1155/humu/6657400","DOIUrl":"https://doi.org/10.1155/humu/6657400","url":null,"abstract":"<p>Incontinentia pigmenti (IP) is a rare hereditary disorder affecting 1.2 in 100,000 live births, predominantly females. Genetic analysis of IP is complicated by a homologous pseudogene, making conventional short-read sequencing challenging. While long-range PCR is typically used to overcome this, skewed X-inactivation detection can also aid in assigning variants to <i>IKBKG</i>. We employed a comprehensive approach, incorporating whole-exome sequencing (WES), long-range PCR, RT-PCR, X-inactivation analysis, and nanopore sequencing, to identify and accurately phase a small heterozygous deletion, NM_001099857.5: c.363_367del, p.(Leu122Glyfs ^∗14), in the <i>IKBKG</i> gene in an IP-affected family. The deletion was initially detected via WES, with skewed X-inactivation observed in both the proband and her mother. Long-range PCR specific to <i>IKBKG</i> confirmed the variant’s location in the <i>IKBKG</i> gene, not in the pseudogene. On the RNA level, the variant was undetectable, suggesting nonsense-mediated decay of the transcript. Nanopore sequencing precisely mapped the variant to <i>IKBKG</i> and analyzed the methylation status of both alleles, confirming the skewed X-inactivation, with the variant-carrying allele predominantly inactivated. This demonstrates the nanopore sequencing’s value in genetic diagnosis, enabling precise variant localization and analysis of X chromosome activation status in females with skewed X-inactivation, aiding in accurate diagnosis and understanding of IP.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/6657400","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole Genome Sequencing of “Mutation-Negative” Individuals With Cornelia de Lange Syndrome","authors":"Morad Ansari,&nbsp;Mihail Halachev,&nbsp;David Parry,&nbsp;Jose L. Campos,&nbsp;Elston N. D’Souza,&nbsp;Christopher Barnett,&nbsp;Andrew O. M. Wilkie,&nbsp;Angela Barnicoat,&nbsp;Chirag V. Patel,&nbsp;Elena Sukarova-Angelovska,&nbsp;Katta M. Girisha,&nbsp;Helen V. Firth,&nbsp;Katrina Prescott,&nbsp;Louise C. Wilson,&nbsp;Meriel McEntagart,&nbsp;Rosemarie Davidson,&nbsp;Sally Ann Lynch,&nbsp;Shelagh Joss,&nbsp;Simon T. Holden,&nbsp;Wayne K. Lam,&nbsp;Sanjay M. Sisodiya,&nbsp;Andrew J. Green,&nbsp;Gemma Poke,&nbsp;Nicola Whiffin,&nbsp;David R. FitzPatrick,&nbsp;Alison Meynert","doi":"10.1155/humu/4711663","DOIUrl":"https://doi.org/10.1155/humu/4711663","url":null,"abstract":"<p>This study was aimed at assessing the diagnostic utility of whole genome sequence analysis in a well-characterised research cohort of individuals referred with a clinical suspicion of Cornelia de Lange syndrome (CdLS) in whom prior genetic testing had not identified a causative variant. Short-read whole genome sequencing was performed on 195 individuals from 105 families, 108 of whom were affected. 100/108 of the affected individuals had prior relevant genetic testing, with no pathogenic variant being identified. The study group comprised 42 trios in which both parental samples were available for testing (42 affected individuals and 126 unaffected parents), 61 singletons (unrelated affected individuals), and two families with more than one affected individual. The results showed that 32 unrelated probands from 105 families (30.5%) had likely causative coding region-disrupting variants. Four loci were identified in &gt; 1 proband: <i>NIPBL</i> (10), <i>ANKRD11</i> (6), <i>EP300</i> (3), and <i>EHMT1</i> (2). Single variants were detected in the remaining genes (<i>EBF3</i>, <i>KMT2A</i>, <i>MED13L</i>, <i>NLGN3</i>, <i>NR2F1</i>, <i>PHIP</i>, <i>PUF60</i>, <i>SET</i>, <i>SETD5</i>, <i>SMC1A</i>, and <i>TBL1XR1</i>). Possibly causative variants in noncoding regions of <i>NIPBL</i> were identified in four individuals. Single de novo variants were identified in five genes not previously reported to be associated with any developmental disorder: <i>ARID3A</i>, <i>PIK3C3</i>, <i>MCM7</i>, <i>MIS18BP1</i>, and <i>WDR18</i>. The clustering of de novo noncoding variants implicates a single upstream open reading frame (uORF) and a small region in Intron 21 in <i>NIPBL</i> regulation. Causative variants in genes encoding chromatin-associated proteins, with no defined influence on cohesin function, appear to result in CdLS-like clinical features. This study demonstrates the clinical utility of whole genome sequencing as a diagnostic test in individuals presenting with CdLS or CdLS-like phenotypes.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/4711663","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Analysis of Complex Structural and Splice-Altering Variants in the ARSB Gene Towards the Personalized Antisense-Based Therapy for Mucopolysaccharidosis Type VI Patients","authors":"Igor Bychkov,&nbsp;Alexandra Filatova,&nbsp;Galina Baydakova,&nbsp;Nataliya Sikora,&nbsp;Emiliya Garifullina,&nbsp;Anna Bykova,&nbsp;Vyacheslav Tabakov,&nbsp;Alexandr Skretnev,&nbsp;Mikhail Skoblov,&nbsp;Ekaterina Zakharova","doi":"10.1155/humu/2250030","DOIUrl":"https://doi.org/10.1155/humu/2250030","url":null,"abstract":"<p>Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the <i>ARSB</i> gene. Herein, we present three patients with biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing of <i>ARSB</i> failed to identify one or both causative variants. RNA analysis of patients’ samples revealed alterations of the wild-type <i>ARSB</i> mRNA isoform in all cases, and one case required further analysis using whole genome sequencing. As a result, we identified one complex structural variant, which is a 52-kb insertion of the <i>LHFPL2</i> gene fragment in the <i>ARSB</i> Intron 4, derived from nonallelic homologous recombination and leading to premature transcription termination, a recurrent deep intronic variant leading to pseudoexon activation and an intragenic deletion altering the integrity and splicing of the <i>ARSB</i> Exon 2.</p><p>Using a minigene-based cellular model, we demonstrated that the identified pseudoexon can be efficiently blocked by antisense molecules incorporated into modified U7 small nuclear RNAs and circular RNAs. The same approach was used to block the overlapping polymorphic pseudoexon in the <i>ARSB</i> gene and increase the amount of wild-type mRNA isoform approximately twofold.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/2250030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143113867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Update on Reported Variants in the Skeletal Muscle α-Actin (ACTA1) Gene","authors":"Joshua S. Clayton,&nbsp;Mridul Johari,&nbsp;Rhonda L. Taylor,&nbsp;Lein Dofash,&nbsp;Georgina Allan,&nbsp;Gavin Monahan,&nbsp;Peter J. Houweling,&nbsp;Gianina Ravenscroft,&nbsp;Nigel G. Laing","doi":"10.1155/2024/6496088","DOIUrl":"https://doi.org/10.1155/2024/6496088","url":null,"abstract":"<p>The <i>ACTA1</i> gene encodes skeletal muscle alpha-actin, which forms the core of the sarcomeric thin filament in adult skeletal muscle. ACTA1 represents one of six highly conserved actin proteins that have all been associated with human disease. The first 15 pathogenic variants in <i>ACTA1</i> were reported in 1999, which expanded to 177 in 2009. Here, we update on the now 607 total variants reported in LOVD, HGMD, and ClinVar, which includes 343 reported pathogenic/likely pathogenic (P/LP) variants. We also provide suggested <i>ACTA1</i>-specific modifications to ACMG variant interpretation guidelines based on our analysis of known variants, gnomAD reports, and pathogenicity in other actin isoforms. Using these criteria, we report a total of 447 P/LP <i>ACTA1</i> variants. From a clinical perspective, the number of reported <i>ACTA1</i> disease phenotypes has grown from five to 20, albeit with some overlap. The vast majority (74%) of <i>ACTA1</i> variants cause nemaline myopathy (NEM), but there are increasing numbers that cause cardiomyopathy and novel phenotypes such as distal myopathy. We highlight challenges associated with identifying genotype–phenotype correlations for <i>ACTA1</i>. Finally, we summarize key animal models and review the current state of preclinical treatments for <i>ACTA1</i> disease. This update provides important resources and recommendations for the study and interpretation of <i>ACTA1</i> variants.</p>","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2024 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/2024/6496088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142525499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}