Human molecular genetics最新文献

{"title":"Genome-wide association study for lung cancer in 6531 African Americans reveals new susceptibility loci.","authors":"Jinyoung Byun, Younghun Han, Jiyeon Choi, Ryan Sun, Vikram R Shaw, Catherine Zhu, Xiangjun Xiao, Christine Lusk, Hoda Badr, Hyun-Sung Lee, Hee-Jin Jang, Yafang Li, Hyeyeun Lim, Erping Long, Yanhong Liu, Linda Kachuri, Kyle M Walsh, John K Wiencke, Demetrius Albanes, Stephen Lam, Adonina Tardon, Marian L Neuhouser, Matt J Barnett, Chu Chen, Stig Bojesen, Hermann Brenner, Maria Teresa Landi, Mattias Johansson, Angela Risch, H-Erich Wichmann, Heike Bickeböller, David C Christiani, Gad Rennert, Susanne Arnold, John K Field, Sanjay Shete, Loic Le Marchand, Geoffrey Liu, Angeline S Andrew, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Fiona Taylor, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Alpa Patel, Xihong Lin, Krista A Zanetti, Curtis C Harris, Stephen Chanock, James McKay, Ann G Schwartz, Rayjean J Hung, Christopher I Amos","doi":"10.1093/hmg/ddaf059","DOIUrl":"https://doi.org/10.1093/hmg/ddaf059","url":null,"abstract":"<p><p>Despite lung cancer affecting all races and ethnicities, disparities are observed in incidence and mortality rates among different ethnic groups in the United States. Non-Hispanic African Americans had a high incidence rate of lung cancer at 55.8 per 100 000 people, as well as the highest death rate at 37.2 per 100 000 people from 2016 to 2020. While previous genome-wide association studies (GWAS) have identified over 45 susceptibility risk loci that influence lung cancer development, few GWAS have investigated the etiology of lung cancer in African Americans. To address this gap in knowledge, we conducted GWAS of lung cancer focused on studying African Americans, comprising 2267 lung cancer cases and 4264 controls. We identified three loci associated with lung cancer, one with lung adenocarcinoma, and four with lung squamous cell carcinoma in this population at the genomic-wide significance level. Among them, three novel loci were identified near VWF at 12p13.31 for overall lung cancer and GACAT3 at 2p24.3 and LMAN1L at 15q24.1 for lung squamous cell carcinoma. In addition, we confirmed previously reported risk loci with known or new lead variants near CHRNA5 at 15q25.1 and CYP2A6 at 19q13.2 associated with lung cancer and TRIP13 at 5p15.33 and ERC1 at 12p13.33 associated with lung squamous cell carcinoma. Further multi-step functional analyses shed light on biological mechanisms underlying these associations of lung cancer in this population. Our study highlights the importance of ancestry-specific studies for the potential alleviation of lung cancer burden in African Americans.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989807","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":"New selective androgen receptor modulator TEI-SARM2 improves muscle function in a Duchenne muscular dystrophy rat model.","authors":"Katsuyuki Nakamura, Masanobu Kanou, Wataru Fujii, Karina Kouzaki, Toshie Jimbo, Keitaro Yamanouchi, Koichi Nakazato, Hiroshi Ueda, Jun Hirata, Kei Yamana","doi":"10.1093/hmg/ddaf028","DOIUrl":"10.1093/hmg/ddaf028","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by a genetic mutation in the Dmd gene. Dystrophin mutant mice (mdx) have traditionally been used for DMD research as a disease model in the preclinical stage; however, mdx mice exhibit only very mild phenotypes to partially mimic muscle degeneration and regeneration. To overcome this limitation in preclinical studies, DMD mutant rats (DMD rats) generated by CRISPR/Cas were used as a DMD model to exhibit age-dependent progressive muscle degeneration and pathophysiological features similar to DMD patients and more severe than those displayed by mdx mice. TEI-SARM2 is a non-steroidal, orally available selective androgen receptor modulator (SARM) developed as a pharmaceutical candidate for the treatment of muscle wasting diseases based on its potent anabolic activity on skeletal muscle mass. In this study, long-term treatment of daily oral administration of TEI-SARM2 to DMD rats significantly improved muscle function (endurance and strength) assessed by grip and tetanic force measurements. TEI-SARM2 did not increase the muscle weight of hindlimbs in male DMD rats; moreover, long-term, weekly oral administration for 24 weeks improved muscle function with reduced side effects on the prostate and testes weight. Histological analysis showed that TEI-SARM2 significantly reduced adipose tissue infiltration in DMD muscle. In female DMD rats, both daily and weekly TEI-SARM2 treatment showed anabolic effects and enhanced muscle strength and endurance. Taken together, these results indicate that TEI-SARM2 has non-anabolic and anabolic effects that improve dystrophic muscle dysfunction and can be a supportive therapeutic option for DMD.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"852-863"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556707","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":"Expression of Concern: Cowden syndrome-associated germline SDHD variants alter PTEN nuclear translocation through SRC-induced PTEN oxidation.","authors":"","doi":"10.1093/hmg/ddaf042","DOIUrl":"10.1093/hmg/ddaf042","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"915"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742758","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":"Nucleoredoxin regulates WNT signaling during pituitary stem cell differentiation.","authors":"Michelle L Brinkmeier, Leonard Y M Cheung, Sean P O'Connell, Diana K Gutierrez, Eve C Rhoads, Sally A Camper, Shannon W Davis","doi":"10.1093/hmg/ddaf032","DOIUrl":"10.1093/hmg/ddaf032","url":null,"abstract":"<p><p>Nucleoredoxin (Nxn) encodes a multi-functional enzyme with oxidoreductase activity that regulates many different signaling pathways and cellular processes in a redox-dependent manner. Rare NXN mutations are reported in individuals with recessive Robinow syndrome, which involves mesomelic skeletal dysplasia, short stature, craniofacial dysmorphisms, and incompletely penetrant heart and palate defects. Here we report that Nxn is expressed in the ventral diencephalon and developing pituitary gland, and that Nxn deficient mice have pituitary dysmorphology and craniofacial abnormalities that include defects in the skull base and cleft palate. Nxn mutant mice exhibit reduced WNT signaling and reduced differentiation of pituitary stem cells into hormone-producing cells. These results suggest patients with Robinow syndrome could benefit from evaluation by endocrinologists for pituitary structural imaging and hormone insufficiency.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"870-881"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566926","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":"A de novo deletion underlying spinal muscular atrophy: implications for carrier testing and genetic counseling.","authors":"Maria M Zwartkruis, Mirjam S de Pagter, Demi Gommers, Marije Koopmans, Cecile P E Ottenheim, Joris V Kortooms, Mirjan Albring, Martin G Elferink, Renske I Wadman, Fay-Lynn Asselman, Inge Cuppen, W Ludo van der Pol, Marcel R Nelen, Gijs W van Haaften, Ewout J N Groen","doi":"10.1093/hmg/ddaf035","DOIUrl":"10.1093/hmg/ddaf035","url":null,"abstract":"<p><p>Spinal muscular atrophy (SMA) is an autosomal recessive disease most commonly caused by homozygous deletion of the SMN1 gene. Parents of affected children are typically carriers, with a recurrence risk of 25% for future pregnancies. Their close relatives have up to 50% chance of being carriers. Carriers typically possess a single copy of the SMN1 gene; however, some parents carry two copies of SMN1. Current standard diagnostic carrier tests are unable to distinguish between silent carriers with two copies on one chromosome (2 + 0 genotype) and non-carriers (1 + 1 genotype), where a de novo deletion occurred. This distinction is crucial for recurrence risk assessment, which highlights the unsolved challenge to carrier testing and genetic counseling. We combined microsatellite marker analysis, SMN copy number analysis, Sanger sequencing, long-read sequencing and de novo assembly to investigate the cause of the absence of SMN1 in a pedigree with an SMA patient identified through newborn screening, whose parents each carried two SMN1 copies. Our analysis revealed that the father is a silent carrier, while de novo assembly of the SMN locus showed a 1.4 megabase (Mb) de novo deletion between mother and child. This deletion encompasses SMN1 and SMN2 and represents the first reported nucleotide-level resolved SMA-causing deletion to date. Our findings allowed informed counseling of at-risk relatives and illustrate the complexity of SMA carrier testing and counseling. This case underscores the feasibility of and need for advanced genetic testing for SMA carriership in select cases, to improve genetic counseling practices, risk assessment, and family planning.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"894-904"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648335","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":"Mate-pair sequencing assisted prenatal counseling for a rare complex chromosomal rearrangement carrier.","authors":"Lu Wan, Zeng Baitao, Tan Yuxin, Chen Zhongfa, Zhou Jihui, Huang Ning, Yang Bicheng, Huang Shuhui, Liu Yanqiu, Yuan Huizhen","doi":"10.1093/hmg/ddaf012","DOIUrl":"10.1093/hmg/ddaf012","url":null,"abstract":"<p><strong>Objective: </strong>This study was aimed to identify a rare complex rearrangement and assist prenatal counseling.</p><p><strong>Method: </strong>Mate-pair sequencing (MPseq) combined with karyotypes, copy number variants sequencing and whole exome sequencing was used to provide accurate chromosome breakpoints and assist prenatal diagnosis for a mentally retarded pregnant woman.</p><p><strong>Result: </strong>MPseq indicated a complex rearrangement involved 25 breakpoints and fusions, disrupting 6 genes. Among which, ZMIZ1 was associated with neurodevelopmental disorders with dysmorphic facies and distal skeletal abnormalities, which was consistent with the phenotype of pregnant women.</p><p><strong>Conclusion: </strong>MPseq was a cost-effective and accurate method that could be used as a complementary tool for human genetic diagnosis and prenatal counseling.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"864-869"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566924","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 role of CSNK1A1 and its de novo mutations in infantile spasms syndrome.","authors":"Decheng Ren, Zhenxi Yang, Juan Hu, Lei Ji, Yan Bi, Fan Yuan, Yang Yan, Jing Peng, Keyi Li, Ke Yang, Liangjie Liu, Xiao Mao, Yingying Luo, Yanlin Wang, Guang He, Kai Li, Ying Peng","doi":"10.1093/hmg/ddaf030","DOIUrl":"10.1093/hmg/ddaf030","url":null,"abstract":"<p><p>Infantile spasms syndrome (ISS) is an early-onset epileptic encephalopathy characterized by uncontrollable seizures, severe electroencephalogram abnormalities, as well as delayed cognitive and behavioral development. Independent studies have shown that a variety of genes are involved in ISS and genetic factors play a critical role in its pathogenesis. Here we report two de novo mutations in the casein kinase 1 isoform alpha (CSNK1A1) gene which underlie severe epilepsy with similar clinical presentation in two patients. The identified variants are one missense mutation c.646G > C (p.Ala216Pro, Mut) in NM_001025105.3 and one deletion c.599_604delACATAC (p.His200_Ile201del, Del). In vitro analyses indicated that the Mut causes significant decreases in both mRNA and protein expression, while the Del demonstrated no significant impact on gene expression level. However, co-immunoprecipitation studies have shown that both mutations lead to reduced interactions between CSNK1A1 and β-catenin, resulting in excessive intracellular β-catenin and aberrant expression of several downstream genes. Compared with the wild type (WT), the EdU positive rates in cells transfected with Mut plasmid or Del plasmid were both elevated. Wnt/β-catenin signaling pathway is crucial to neurogenesis. An abnormal rise in β-catenin level has been utilized to generate genetic models for ISS. Our results not only elucidate the role of a novel candidate gene CSNK1A1 in the pathology of ISS, but also provide further evidence for the findings that mediating Wnt/β-catenin signaling is a potential mechanism causing ISS.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"905-913"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742764","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":"LRP8 inhibits bladder cancer cell ferroptosis by activating the Wnt/β-catenin-SCD1 positive feedback loop.","authors":"Yong Zhao, Guohong Shi, Xiang Huang, Zhongyuan Zhang, Kaijun Liao, Hao Xiong, Zhiqiang Feng, Shihui Mao, Xu Zhang","doi":"10.1093/hmg/ddaf024","DOIUrl":"10.1093/hmg/ddaf024","url":null,"abstract":"<p><strong>Background: </strong>Advanced bladder cancer (bc) patients often have poor prognoses due to issues such as recurrence and drug resistance. The discovery of ferroptosis has opened new avenues for bc treatment; however, the specific regulatory mechanisms remain to be explored. This study aimed to investigate the mechanisms influencing ferroptosis in bc cells, with a particular focus on the role of low-density lipoprotein receptor-related protein 8 (LRP8).</p><p><strong>Methods: </strong>We utilized reverse transcription-quantitative polymerase chain reaction and western blot to assess the expression of LRP8 in bc cells, activation of the Wnt/β-catenin signaling pathway, and the expression of genes related to fatty acid synthesis. We measured changes in ferroptosis levels by evaluating mitochondrial membrane potential, Fe2+, malondialdehyde, and reactive oxygen species levels. A xenograft mouse model was employed to validate the impact of LRP8 on bc progression.</p><p><strong>Results: </strong>Cell experiments demonstrated a significant upregulation of LRP8 expression in bc cells. Knockdown of LRP8 induced ferroptosis in bc cells, a process directly triggered by the inhibition of the Wnt/β-catenin signaling pathway. Activation of the Wnt/β-catenin signaling pathway mediated by LRP8 upregulated the expression of stearoyl-CoA desaturase 1 (SCD1), subsequently leading to the suppression of ferroptosis. In vivo experiments indicated that LRP8 knockdown significantly impaired bc growth, accompanied by inhibition of the Wnt/β-catenin-SCD1 axis.</p><p><strong>Conclusion: </strong>LRP8 mediates the synthesis of monounsaturated fatty acids through the Wnt/β-catenin-SCD1 positive feedback loop, thereby inhibiting ferroptosis in bc cells. These findings provide a promising target for the regulation of ferroptosis in bc cells.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"843-851"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482044","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":"Expression of Concern: Naturally occurring germline and tumor-associated mutations within the ATP-binding motifs of PTEN lead to oxidative damage of DNA associated with decreased nuclear p53.","authors":"","doi":"10.1093/hmg/ddaf041","DOIUrl":"10.1093/hmg/ddaf041","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"914"},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12056306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742760","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":"UNRAVELING CLN7 disease: the distinct roles of two close MFSD8/CLN7 splice variants in phenotypic expression.","authors":"Ana Clara Venier, Sofía Savy, Gerardo Carro, Guillermo Guelbert, Ezequiel Grondona, Norberto Guelbert, Juan Pablo Nicola, Favio Pesaola, Ana Lucía De Paul","doi":"10.1093/hmg/ddaf067","DOIUrl":"https://doi.org/10.1093/hmg/ddaf067","url":null,"abstract":"<p><p>CLN7 is a lysosomal storage disease caused by pathogenic variants in the MFSD8/CLN7 gene. Typically neurodegenerative, patients present seizures and developmental delay since 2-6 years of age and a rapid psychomotor, verbal, and visual deterioration that leads to premature death. However, 'atypical' cases have also been reported. Although more than 80 DNA variants in the MFSD8/CLN7 gene have been reported, no data about a genotype/phenotype correlation is available. Here, we analyze five 'classical' and 'atypical' CLN7 patients by molecular and computational methods. Four variants have been found: c.103C > T (p.Arg35*, pathogenic), c.1394G > A (p.Arg465Gln, pathogenic), c.863 + 1G > A (likely pathogenic), and c.863 + 4A > G (of uncertain significance). Both splice variants showed altering of the splicing process on a minigene reporter assay. Furthermore, exon 8 was deleted in the MFSD8/CLN7 cDNA of blood samples from two patients carrying the splicing variants, demonstrating their effect. The c.863 + 4A > G variant also showed a residual wildtype MFSD8/CLN7 expression and, thus, explaining the milder phenotype. Finally, a clustered geographical distribution of the c.103C > T and c.863 + 4A > G variants was observed in the northeast and center of Argentina, respectively. Our data confirm the pathogenicity of the c.863 + 1G > A variant and reclassify the c.863 + 4A > G variant as pathogenic by adding experimental data, offering new information for a precise prognosis, and expanding the genetic and epidemiological spectrum of CLN7 in the South American region. Ultimately, we seek to raise awareness about the existence of this pathology in the region to reduce the so-called 'diagnostic odyssey' in pediatric patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002128","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}