Human molecular genetics最新文献

{"title":"Improving genetic diagnostic yield in familial and sporadic cerebral cavernous malformations: detection of copy number and deep Intronic variants.","authors":"Neblina Sikta, Samuel Gooley, Timothy E Green, Olivia Hoeper, Tom Witkowski, Caitlin Bennett, David Francis, Joshua Reid, Kevin Mao, Mohammed Awad, Samuel Roberts-Thomson, Kristian Bulluss, Jonathan Clark, Ingrid E Scheffer, Piero Perucca, Mark F Bennett, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand","doi":"10.1093/hmg/ddaf077","DOIUrl":"10.1093/hmg/ddaf077","url":null,"abstract":"<p><p>Cerebral cavernous malformations (CCMs) are intracranial vascular lesions associated with risk of haemorrhages and seizures. While the majority are sporadic and often associated with somatic variants in PIK3CA and MAP3K3, around 20% are familial with germline variants in one of three CCM genes-KRIT1/CCM1, CCM2 and PDCD10/CCM3. We performed comprehensive phenotyping and genetic analysis of nine multiplex families and ten sporadic individuals with CCM. In the familial cases, initial standard analyses had a low yield, we therefore searched for small copy number changes and deep intronic variants. Subsequently, pathogenic germline variants in KRIT1/CCM1 or CCM2 were identified in all 9 multiplex families. Single or multiple exon deletions or splice site variants in KRIT1/CCM1 were found in 3/9 families. Where cavernous malformation tissue was available, second hit somatic PIK3CA variants were identified in 4/7 individuals. These 4 individuals were from separate families with germline KRIT1/CCM1 variants. In 8/10 sporadic cases, we detected recurrent pathogenic somatic PIK3CA, MAP3K3 or CCM2 variants. All familial cases had multiple CCMs, whereas the sporadic cases had a single lesion only, which was in the temporal lobe in 9/10 individuals. Our comprehensive approach interrogating deep intronic variants combined with detection of small copy number variants warrants implementation in standard clinical genetic testing pipelines to increase diagnostic yield. We also build on the established second hit germline and somatic variant mechanism in some CCM lesions. Genetic diagnosis has clinical implications such as reproductive counselling and provides potential eligibility for precision medicine therapies to treat rapidly growing CCMs.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1286-1293"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119527","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":"The p.W651fsX666 mutation on COL10A1 results in impaired trimerization of normal collagen X to induce Schmid type Metaphyseal chondrodysplasia.","authors":"Jingye Yang, Jing Zhang, Qingxiang Lu, Haiying Tian, Ke Wang, Zhi Liu, Yu Xiong, Yadong Li, Ning Ma, Hongxia Tian, Zhongxue Zhou, Ding'an Zhou","doi":"10.1093/hmg/ddaf071","DOIUrl":"10.1093/hmg/ddaf071","url":null,"abstract":"<p><p>Haploinsufficiency resulting from the degradation of mutant Collagen Type X Alpha 1 Chain (COL10A1) mRNA by nonsense-mediated decay (NMD) has been attributed to the pathogenesis of Schmid-type metaphyseal chondrodysplasia (SMCD) in cases involving nonsense mutations. However, this mechanism does not fully explain the complexity of SMCD. In this study, we identified a c.1951_1952 InsT (p.W651 fsX666) mutation in exon 3 of COL10A1 that is associated with chondrodysplasia phenotypes in a two-generation family with SMCD. The mRNA decay of the mutant COL10A1 (named as affected E666X-COL10A1) is caused by the p.W651fsX666 mutation, which also disrupts the trimerization of normal collagen X. However, the mutant mRNA decay of affected exogenous E666X-COL10A1, as well as the complete degradation of E666X-COL10A1 mRNA in the proband, is not significantly induced by the W651fsX666 mutation. In vitro trimerization analyses results indicate that the trimerization of normal collagen X and wild-type collagen X are disrupted by W651fsX666 and E666X-collagen X mutations, respectively, suggesting that the mutant allele collagen X may impose a dominant-negative effect on the normal collagen X. Our results are the first to reveal that the impaired trimerization of normal collagen X is caused by the W651fsX666 mutation and a dominant-negative effect on the normal allele collagen X exerted by the mutant allele collagen X, causing impaired trimerization of collagen X, which will interpret the phenotype variability among the affected individuals in the pedigree with metaphyseal chondrodysplasia type Schmid (MCDS) studied.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1265-1285"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119528","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":"The NeflE397K mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E.","authors":"Dennis O Pérez-López, Audrey A Shively, F Javier Llorente Torres, Roxanne Muchow, Zaid Abu-Salah, Mohammed T Abu-Salah, Jackson T Veltrop, Michael L Garcia, Catherine L Smith, D D W Cornelison, Nicole L Nichols, Monique A Lorson, Christian Lorson","doi":"10.1093/hmg/ddaf080","DOIUrl":"10.1093/hmg/ddaf080","url":null,"abstract":"<p><p>Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated two orthologous NEFLE396K mutation in the mouse C57BL/6 J background, NeflE397K. In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in NeflE397K mice. In this manuscript, we report our characterization of NeflE397K motor function deficits, muscle pathology and changes in breathing. Nefl+/E397K and NeflE397K/E397K mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl+/E397K and NeflE397K/E397K mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. NeflE397K/E397K mice phenotypes and pathology were consistently more severe than Nefl+/E397K mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1313-1327"},"PeriodicalIF":3.1,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142446","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":"Novel TMEM53 missense variant generated a new ubiquitination site and cause Craniotubular dysplasia, Ikegawa type.","authors":"Ying Peng, Zhengqing Wan, Kai Li, Zhen Liu, Jing Chen, Ai Hu, Silong Wang, Rui Liu, Bo Li, Xiao Mao, Ming Wu","doi":"10.1093/hmg/ddaf121","DOIUrl":"https://doi.org/10.1093/hmg/ddaf121","url":null,"abstract":"<p><p>Genetic mutations in the TMEM53 gene have been linked to Craniotubular Dysplasia, Ikegawa Type (CTDI). To elucidate the etiology in a consanguineous family exhibiting the typical clinical phenotype of CTDI, trio whole exome sequencing (Trio-WES) was conducted, and a homozygous missense variant in the TMEM53 gene (NM_024587.4: c.634G > A: p.E212K) was identified. Both cellular experiments and patient blood sample analyses demonstrated that the p.E212K variant leads to the complete absence of TMEM53 protein. Further studies on ubiquitination confirmed that this variant introduced a novel ubiquitination site, causing protein degradation through the ubiquitin-proteasome system (UPS), resulting in TMEM53 protein deficiency. To our knowledge, this is the inaugural report of a missense variant creating a novel post-translational ubiquitination site that causes a Mendelian disease. This finding underscores the critical role of examining changes in post-translational modifications (PTMs) in determining the pathogenicity of gene variants.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663893","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":"Heart is the most susceptible organ in an isogenic background to loss of function mutations in the mitochondrial metallochaperone SCO1.","authors":"Sampurna Ghosh, Kimberly A Jett, Zakery N Baker, Aren Boulet, Amzad Hossain, Stanley A Moore, Martina Ralle, Binbing Ling, Paul A Cobine, Scot C Leary","doi":"10.1093/hmg/ddaf123","DOIUrl":"https://doi.org/10.1093/hmg/ddaf123","url":null,"abstract":"<p><p>SCO1 is a nuclear-encoded protein with roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. It remains unclear, however, why mutations in this ubiquitously expressed gene product cause distinct, tissue-specific forms of disease that primarily affect heart, liver or brain function. To gain a better understanding of the clinical heterogeneity observed across SCO1 pedigrees, we deleted Sco1 in the murine brain and observed a severe COX deficiency in the absence of altered tissue copper content that was tied to early, neonatal lethality. We therefore transitioned to whole body knockin mice expressing allelic variants of SCO1 that are pathogenic in humans to more accurately reflect the patient condition and avoid the lethality associated with tissue-specific Sco1 knockout. Sco1M277V mice exhibited the most severe COX deficiency in their brain, modeling the pathophysiological consequences of the p.Met294Val variant in humans and supporting the idea that the primary role of SCO1 in this tissue is to promote COX assembly. Phenotyping of Sco1G115S, Sco1P157L and Sco1M277V mice nonetheless emphasized that the heart generally displayed the most severe, combined COX and copper deficiency, with Sco1G115S and Sco1P157L hearts developing a dilated cardiomyopathy that was accompanied by significant depletion of their mitochondrial copper pool. Taken together, our findings suggest that in an isogenic context the heart is the most susceptible organ to loss of SCO1 function, and that single nucleotide polymorphisms at modifier loci in an outbred population likely contribute to the clinical heterogeneity observed across SCO1 pedigrees.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659050","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":"Novel compound heterozygous variants in NBAS underlying fever-dependent infantile liver failure syndrome type 2: potential implications of protein thermostability.","authors":"Jiexin Tang, Xiaoru Wang, Hongmei Qiu, Lin Wei, Yuan Gao, Yan Sun","doi":"10.1093/hmg/ddaf120","DOIUrl":"https://doi.org/10.1093/hmg/ddaf120","url":null,"abstract":"<p><strong>Background & aims: </strong>Infant liver failure syndrome type 2 (ILFS2), a rare autosomal recessive disorder manifesting as recurrent acute liver failure (ALF) triggered by febrile illness, is associated with neuroblastoma amplified sequence (NBAS) mutations. This study employs molecular dynamics simulation (MDS) to investigate how missense variants in the Sec39 domain influence protein conformation and thermostability.</p><p><strong>Approach & results: </strong>We identified novel compound heterozygous variants in the NBAS gene, c.2231 T > C (p.Leu744Pro) and c.2266C > T (p.Arg756Cys), in two Chinese siblings diagnosed with ILFS2. According to ACMG guideline, both variants were initially classified as variants of uncertain significance. To elucidate the potential functional impact, MDS was performed to compare structural dynamics between wild-type (WT) and mutant (MUT) NBASs at physiological temperature (37°C) and under thermal stress (42°C). The results revealed distinct thermal responses. WT demonstrated robust thermotolerance, with comparable trajectory patterns and curve parameters across two temperatures. In contrast, specific variants induced localized conformational perturbations and secondary structural reorganization. Notably, while MUT exhibited kinetic profiles similar to WT at 37°C, it showed pronounced fluctuations in flexible regions under thermal stress, with disrupted hydrogen-bonding networks and significant conformational changes, indicating compromised thermostability.</p><p><strong>Conclusions: </strong>The diagnosis of ILFS2 primarily relies on clinical presentation and genetic confirmation. Although the exact pathogenesis remains unclear, our findings suggest that temperature-sensitive structural destabilization induced by missense mutations within the Sec39 domain of NBAS probably underlies the fever-associated ALF. This provides critical guidance for subsequent protein structural elucidation and mechanism research, and regions exhibiting significantly reduced thermostability represent promising therapeutic targets.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663892","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":"Functional analysis of novel MMP21 gene compound heterozygous mutations in a prenatal case with heterotaxy.","authors":"Quan Chen, Hao Zhang, Xue Li, Lin Liu, Zhiqing Hu, Zhihong Xu","doi":"10.1093/hmg/ddaf122","DOIUrl":"https://doi.org/10.1093/hmg/ddaf122","url":null,"abstract":"<p><strong>Background: </strong>Heterotaxy is a class of congenital disorders resulting from failure to establish normal left-right asymmetry during embryonic development, which causes abnormal positioning and morphology of the thoraco-abdominal organs. The pathogenesis of heterotaxy is multifactorial and involves both genetic and environmental factors. With the application of whole exome sequencing (WES), pathogenic biallelic variants in the matrix metalloproteinase 21 (MMP21) gene have been increasingly identified in patients with heterotaxy and congenital heart defects.</p><p><strong>Methods: </strong>In this study, two novel compound heterozygous MMP21 variants, specifically, a frame shift variant c.414del; p.(Arg139Glufs*38) and an intron variant c.980-16 T > A, were identified in a fetus diagnosed with heterotaxy through WES. In vitro assays were performed to evaluate the effects of the two variants.</p><p><strong>Results: </strong>Western blotting revealed that c.414del variant resulting in premature translation termination and the production of a truncated protein, which was found to completely lack the hemopexin-like repeats domain and to almost entirely lose its catalytic domain. In silico analysis and minigene assay suggested that c.980-16 T > A variant lead to aberrant splicing pattern including exon 5 skipping and 14-bp intron retention. To our knowledge, both of the two variants were reported for the first time, and the c.980-16 T > A is the first intron variant founded to affect splicing in the MMP21 gene.</p><p><strong>Conclusion: </strong>Functional analysis confirmed the pathogenicity of the two variants. Our findings expand the mutational spectrum of MMP21 and provide support for the critical role of MMP21 gene in heterotaxy and congenital heart defects.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659049","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":"A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly.","authors":"Tanveer Abbas, Huan Zhang, Hao Yin, Ma Ao, Ye Jingwei, Nisar Ahmad, Ranjha Khan, Ghulam Murtaza, Ansar Hussain, Fazal Rahim Dawar, Imtiaz Ali, Aurang Zeb, Wasim Shah, Hui Ma, Yuanwei Zhang, Qinghua Shi","doi":"10.1093/hmg/ddaf070","DOIUrl":"https://doi.org/10.1093/hmg/ddaf070","url":null,"abstract":"<p><p>Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of male infertility, linked to defective spermiogenesis. Several flagella-associated proteins have been identified as crucial for the proper organization of the sperm flagellar axoneme. We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan. To validate the pathogenicity of this mutation, we developed a Cfap58 mutant mouse model to mimic the patient mutation. The Cfap58M/M mice exhibited infertility and recapitulated the MMAF phenotype observed in human patients. Transmission electron microscopy (TEM) analysis revealed the absence of the central pair (CP) of microtubules in the axonemal structure of sperm flagella. Further analysis demonstrated that the CFAP58 mutation disrupts CP assembly during spermiogenesis, leading to disorganization of axonemal proteins in both human and mouse sperm flagella. Our findings underscore the essential and conserved role of CFAP58 in sperm axoneme assembly and suggests that CFAP58 can serve as a genetic screening marker in the diagnosis and genetic counseling of MMAF and male infertility.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659048","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":"Copy number variants and their implications for developmental and behavioural problems in cleft lip and/or palate.","authors":"Alexandros Rammos, Rachel Blakey, Charlotte A Dennison, Sarah J Lewis, Nabila Ali, Amy Davies, Yvonne Wren, Kerry Humphries, Jonathan Sandy, Elliott Rees, Kimberley Marie Kendall, Gemma C Sharp, Michael J Owen, Marianne B M van den Bree, Evie Stergiakouli","doi":"10.1093/hmg/ddaf115","DOIUrl":"https://doi.org/10.1093/hmg/ddaf115","url":null,"abstract":"<p><p>Cleft lip and/or palate (CL/P) is the most common craniofacial congenital anomaly and has been associated with higher risk of neurodevelopmental and behavioural problems indicating potential shared genetic factors between CL/P and neurodevelopmental disorders. In this study, we aimed to determine the prevalence of neurodevelopmental copy number variants (CNV) in children with CL/P and their link to early developmental and behavioural problems. Using data from the Cleft Collective, the largest UK-based national cohort study of children with CL/P, we determined the rates of neurodevelopmental CNVs in children with CL/P comparing them to the general population, explored differences by cleft type and investigated risk of developmental delays and behavioural problems among those with CL/P and neurodevelopmental CNVs. Children with CL/P had a higher prevalence of neurodevelopmental CNVs than participants in four population-based samples (3.7% vs 2.3% in the Avon Longitudinal Study of Parents and Children (ALSPAC), 2.0% in Born in Bradford (BiB), 2.3% in Millenium Cohort Study (MCS), 1.7% in UK Biobank, ORs(95%CIs): ALSPAC = 1.56(1.18-2.06), BiB = 1.84(1.37-2.45), MCS = 1.59(1.19-2.11), UK Biobank = 2.15(1.68-2.71). Children with cleft palate only were 3 times more likely to have a neurodevelopmental CNV (95%CIs1.50-6.59, p = 0.03) than children with cleft lip only. Furthermore, children with CL/P and neurodevelopmental CNVs were more likely to experience early developmental delays and behavioural problems by age 5 compared to children with CL/P and without neurodevelopmental CNVs. These findings highlight that genetic testing ascertaining the presence of neurodevelopmental CNVs might be helpful in early identification of developmental needs in children with CL/P.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636928","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":"Pathology of three ALS patients with FUS variants, including one likely benign Q23L variant lacking FUS inclusions.","authors":"Erica Stenvall, Kornelia Åman Grönlund, Zdenek Rohan, Per Zetterström, Angelica Nordin, Karin Forsberg","doi":"10.1093/hmg/ddaf119","DOIUrl":"https://doi.org/10.1093/hmg/ddaf119","url":null,"abstract":"<p><p>Fused in sarcoma (FUS) is an RNA-binding protein implicated in juvenile amyotrophic lateral sclerosis (ALS). Mutations in the FUS gene, particularly those affecting the nuclear localization signal (NLS), impair nuclear import and lead to cytoplasmic accumulation of FUS inclusions in motor neurons. However, the pathological and clinical significance of FUS variants outside the NLS remains less understood. Here, we describe clinical and histopathological findings from three ALS patients carrying FUS variants: two with NLS-region variants (R495X and P525L), and one with a variant in the N-terminal region outside the NLS (Q23L). The patients carrying NLS variants presented with aggressive, juvenile-onset spinal and bulbar ALS, characterized primarily by lower motor neuron involvement and rapid disease progression. In contrast, the Q23L patient exhibited a slowly progressive disease course, with predominantly upper motor neuron signs. Neuropathological analysis revealed cytoplasmic FUS inclusions in motor neurons of patients with NLS variants, consistent with typical FUS pathology. In contrast, the Q23L patient lacked FUS inclusions and instead displayed pTDP-43 pathology in the hippocampus, neocortex (including the motor cortex), nucleus olivaris, lentiform nucleus, striatum, and some lower motor neurons. Taken together, these results suggest that Q23L is most likely a benign variant. As antisense oligonucleotides (ASOs) targeting FUS are currently being explored in clinical trials, further neuropathological investigations are needed to determine whether ASO-mediated FUS silencing would be effective for patients carrying FUS variants outside the NLS region.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636929","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}