Human molecular genetics最新文献_第4页

Novel PNLDC1 mutations underlie nonobstructive azoospermia in humans and mice. 新的PNLDC1突变是人类和小鼠非阻塞性无精子症的基础。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf136

Meftah Uddin, Li Ming, Feng Wan, Wasim Shah, Mujahid Husain, Muhammad Shoaib, Abu Mansoor, Zhang Huan, Ghulam Mustafa, Fazal Rahim, Aurang Zeb, Yousaf Raza, Muhammad Lateef, Ansar Hussain, Hui Ma, Tanveer Abbas, Amjad Ullah Khan, Ye Jing Wei, Hao Yin, Haibin Guo, Qinghua Shi

{"title":"Novel PNLDC1 mutations underlie nonobstructive azoospermia in humans and mice.","authors":"Meftah Uddin, Li Ming, Feng Wan, Wasim Shah, Mujahid Husain, Muhammad Shoaib, Abu Mansoor, Zhang Huan, Ghulam Mustafa, Fazal Rahim, Aurang Zeb, Yousaf Raza, Muhammad Lateef, Ansar Hussain, Hui Ma, Tanveer Abbas, Amjad Ullah Khan, Ye Jing Wei, Hao Yin, Haibin Guo, Qinghua Shi","doi":"10.1093/hmg/ddaf136","DOIUrl":"10.1093/hmg/ddaf136","url":null,"abstract":"PIWI-interacting RNAs (piRNAs) are small regulatory RNAs (21-35 nucleotides) exclusively expressed in germ cells, where they play a critical role in transposable element repression and post-meiotic gene regulation. The poly(A)-specific RNase-like domain-containing 1 (PNLDC1) protein is essential for piRNA maturation, specifically in 3'-end trimming. Disruption of PNLDC1 has been implicated in nonobstructive azoospermia (NOA) and male infertility. Through whole-exome sequencing, we identified a compound heterozygous mutation (MT1 c.449G > A, p.Trp150* and MT2 c.821A > G, p.His274Ala) in a Chinese NOA patient (P9241) and a homozygous nonsense mutation (MT3 c.1288C > T, p.Arg430*) in a Pakistani NOA patient (II:2) born to a consanguineous couple. Mutant PNLDC1 mRNA was detected, but not the corresponding protein, was detected in the testes of P9241. In contrast, truncated PNLDC1 protein was observed in HEK293T cells transfected with a plasmid harboring mutation MT3. To investigate the functional consequences, we generated a Pnldc1KI/KI mouse model mimicking the MT3 using CRISPR/Cas9 genome editing, which exhibited infertility due to spermiogenesis arrest, phenocopying the NOA condition in patient II:2. Notably, Pnldc1KI/KI testes showed significant derepression of the retrotransposon LINE1 and increased spermatid apoptosis. These findings provide strong functional evidence that PNLDC1 mutations disrupt piRNA biogenesis, impair spermatogenesis, and underlie NOA in both humans and mice.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1753-1764"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951967","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}

引用次数: 0

Refining rare disease variant discovery in an isolated Andean community through imputation-enhanced IBD and kinship inference from whole exome sequencing data. 通过从全外显子组测序数据中推断IBD和亲属关系，在孤立的安第斯社区中改进罕见疾病变异发现。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf132

Cristian Camilo Gaviria-Sabogal, Ingrid Tatyana Bernal, Yasmín Sánchez-Gómez, William Usaquén, Andrea Casas-Vargas, Nora Contreras Bravo, Adrien Morel, Dora J Fonseca-Mendoza, Carlos M Restrepo, Rodrigo Cabrera

{"title":"Refining rare disease variant discovery in an isolated Andean community through imputation-enhanced IBD and kinship inference from whole exome sequencing data.","authors":"Cristian Camilo Gaviria-Sabogal, Ingrid Tatyana Bernal, Yasmín Sánchez-Gómez, William Usaquén, Andrea Casas-Vargas, Nora Contreras Bravo, Adrien Morel, Dora J Fonseca-Mendoza, Carlos M Restrepo, Rodrigo Cabrera","doi":"10.1093/hmg/ddaf132","DOIUrl":"10.1093/hmg/ddaf132","url":null,"abstract":"Rare genetic diseases pose significant diagnostic challenges, especially in geographically isolated populations where consanguinity, founder effects, and novel variants often influence disease patterns. Whole-exome sequencing (WES) is standard practice for rare disease diagnostics, but its limited coverage of noncoding regions limits inheritance-by-descent (IBD) and Runs of Homozygosity (RoH) inference. In this study, we tested an imputation-enhanced IBD and RoH detection method using WES data of 84 individuals from 51 families in Boyacá, Colombia-an Andean region with complex admixed American ancestry. By leveraging large, multi-ancestry reference panels to impute genotypes and increase variant distribution, we achieved improved detection of IBD and RoH regions, with KING showing the best results among the different tools that were tested. Imputation with the 1000 Genome reference panel underperformed compared to raw WES data, whereas large reference panels with diverse ancestry showed the best performance. By integrating these refined IBD results with pedigree information, we identified cryptic family relationships, clarified the role of consanguinity, and improved the prioritization of candidate variants. Our findings show that imputation-enhanced IBD analyses can bolster the utility of WES for rare disease studies, contributing to more accurate and timely genetic diagnoses.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1733-1743"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144859133","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}

引用次数: 0

Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles. 肋肌在骨骼肌病理生理中的双向作用。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf127

Glen B Banks, Darren R Bisset, Jeffrey S Chamberlain

{"title":"Bidirectional role of Costameres in the pathophysiology of mdx skeletal muscles.","authors":"Glen B Banks, Darren R Bisset, Jeffrey S Chamberlain","doi":"10.1093/hmg/ddaf127","DOIUrl":"10.1093/hmg/ddaf127","url":null,"abstract":"Skeletal muscles in Duchenne Muscular Dystrophy (DMD) are most susceptible to injury at a point in maturation when dystrophin is absent and utrophin dissipates from the membrane. The lack of the dystrophin glycoprotein complex (DGC) leaves a residual costameric scaffold that structurally connects the peripheral sarcomeres to the sarcolemma. However, the residual costameres are weak and transmit less lateral force making it unclear how they contribute to the pathophysiology of DMD. Here we found that costameres were near absent in mature mdx4cv:desmin double knockout (dko) fast 2b myofibers where the compensating utrophin protein is not upregulated at costameres. The lack of costameres decoupled sarcomere strain injury from tearing the membrane leading to isolated necrotic myofibers. Despite a 30% reduction in the proportion of myofibers with centrally located nuclei (a marker of degenerating/regenerating myofibers), the fast 2b dko muscles were atrophic and profoundly weakened by the sarcomere strain injury. Thus, our data is consistent with the DGC protecting the membrane and peripheral sarcomeres from the bidirectional forces that propagate through the desmin-fortified costameres.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1681-1692"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144759896","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}

引用次数: 0

Loss of function variants in TMPRSS7 linked to a neurodevelopmental disorder disrupt synaptic function. 与神经发育障碍相关的TMPRSS7功能变异丧失会破坏突触功能。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf137

Weiliang Lu, Shuyuan Li, Songchang Chen, Bingxin Yang, Xiang Qiu, Xianling Cao, Jian Wang, He-Feng Huang, Chenming Xu, Jinglan Zhang

{"title":"Loss of function variants in TMPRSS7 linked to a neurodevelopmental disorder disrupt synaptic function.","authors":"Weiliang Lu, Shuyuan Li, Songchang Chen, Bingxin Yang, Xiang Qiu, Xianling Cao, Jian Wang, He-Feng Huang, Chenming Xu, Jinglan Zhang","doi":"10.1093/hmg/ddaf137","DOIUrl":"10.1093/hmg/ddaf137","url":null,"abstract":"The molecular etiology of more than half of neurodevelopment disorders remains unknown. In this study, we identified recessive variants in the TMPRSS7 gene in a fetus from a non-consanguineous Chinese family with a history of recurrent central nervous system (CNS) malformations, as the likely genetic cause of a neurodevelopmental disorder. TMPRSS7 encodes matriptase-3, a type II transmembrane serine protease (TTSP) that becomes active when its catalytic domain is released outside the cell. During the proteolytic process, the canonical RV(I)V(I)G motif is cleaved, converting the inactive single-chain zymogen into its active form. This activation is closely temporally coupled with TTSPs shedding and ultimately leads to the release of the catalytic domain into the extracellular space to exert its function. The patient carrying compound heterozygous variants in the TMPRSS7 gene, p.R479H and p.S685Kfs*26, exhibited impaired synthesis of the matriptase-3 protease zymogen and defective shedding of the functional serine protease domain. Tmprss7 homozygous knockout (KO) mice exhibited dysregulated synaptic dendritic spine density, function, and dendritic elongation in the cerebral cortex and hippocampus. In addition, the KO animals displayed neurobehavioral deficits, including impairments in spatial learning, anxiety-like behavior, and a reduced preference for social novelty. Multi-omics analysis discovered enrichment of pathways related to synaptic signaling disruptions in both the cerebral cortex and hippocampus. Collectively, our findings identify TMPRSS7 as a candidate gene essential for normal neurodevelopment, highlighting its potential role in the molecular pathogenesis of neurodevelopmental disorders.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1705-1717"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834952","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}

引用次数: 0

Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1. 1型强直性肌营养不良患者代谢功能障碍和肝脏疾病的转录组改变

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf124

Aono Fukumoto, Tomoki Yamanaka, Motoaki Yanaizu, Masayuki Nakamori, Manami Hama, Yoshiaki Yasumizu, Kana Shiotsu, Tsuyoshi Matsumura, Curtis A Nutter, Tomoya Kubota, Harutoshi Fujimura, Yoshihiro Kino, Maurice S Swanson, Kimiko Inoue, Masanori P Takahashi

{"title":"Transcriptome alterations underlying metabolic dysfunction and liver disease in myotonic dystrophy type 1.","authors":"Aono Fukumoto, Tomoki Yamanaka, Motoaki Yanaizu, Masayuki Nakamori, Manami Hama, Yoshiaki Yasumizu, Kana Shiotsu, Tsuyoshi Matsumura, Curtis A Nutter, Tomoya Kubota, Harutoshi Fujimura, Yoshihiro Kino, Maurice S Swanson, Kimiko Inoue, Masanori P Takahashi","doi":"10.1093/hmg/ddaf124","DOIUrl":"10.1093/hmg/ddaf124","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the DMPK 3'-untranslated region, affecting multiple organs, including the skeletal muscles, eyes, heart, central nervous system, and endocrine system. A major pathogenic event in DM1 is the sequestration of muscleblind-like (MBNL) proteins by CUG repeat-containing RNAs transcribed from expanded repeats. Among the various symptoms of DM1, lipid abnormalities and liver dysfunction are frequent but remain understudied. Although abnormal splicing of insulin receptor RNA is implicated, it cannot fully explain these abnormalities. To investigate the molecular mechanisms, we performed transcriptome analysis of postmortem livers from patients with DM1 and Mbnl-knockout mice. RNA-sequencing revealed differentially expressed genes (DEGs) and aberrant splicing in DM1 livers. A comparison of Mbnl1- and Mbnl2-knockout mouse livers indicated that MBNL1 accounts for some of the transcriptomic changes observed in patients with DM1. The DEGs included those related to lipid metabolism and liver fibrosis. DM1-associated changes in the liver transcriptome partially resolved sexual dimorphism in gene expression and uncovered distinct sex-specific pathway alterations. Besides the known MBNL-regulated genes, those related to lipid and glucose metabolism were identified in the aberrant splicing clusters detected in DM1. A correlation between serum gamma-glutamyl transferase levels and overall splicing abnormalities was observed, linking splicing changes in the liver to clinical abnormalities. These findings provide new insights into the molecular basis of DM1-related metabolic and hepatic abnormalities, enhancing our understanding of the systemic effects of this disease.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1718-1732"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834954","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}

引用次数: 0

Genetic nurture: estimating the direct genetic effects of pediatric anthropometric traits. 遗传培养：估计儿童人体测量特征的直接遗传效应。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-05 DOI: 10.1093/hmg/ddaf117

Samuel Ghatan, Jard de Vries, Jean-Baptiste Pingault, Vincent W Jaddoe, Charlotte Cecil, Janine F Felix, Fernando Rivadeneira, Carolina Medina-Gomez

{"title":"Genetic nurture: estimating the direct genetic effects of pediatric anthropometric traits.","authors":"Samuel Ghatan, Jard de Vries, Jean-Baptiste Pingault, Vincent W Jaddoe, Charlotte Cecil, Janine F Felix, Fernando Rivadeneira, Carolina Medina-Gomez","doi":"10.1093/hmg/ddaf117","DOIUrl":"10.1093/hmg/ddaf117","url":null,"abstract":"Parental genetic variants can indirectly influence the traits of their child through the environment, a concept termed 'genetic nurture', or indirect genetic effects (IGE). This study estimated the direct genetic effects (DGE), via direct allelic transmission, and IGE shaping height, body mass index (BMI), and bone mineral density (BMD) in a multi-ethnic Dutch pediatric cohort, examining children with repeated measurements at ages six, nine, and thirteen. We imputed missing parental alleles from the phased haplotypes of 1 931 478 variants (MAF > 1%), utilizing snipar (single nucleotide imputation of parents). We constructed polygenic risk scores (PRSs) and jointly regressed the proband's trait on their own PRS, while controlling for the proband's maternal and paternal PRSs. A total of 4488 probands, with genetic data, underwent at least one of the three specified measurements. We found statistically significant DGE estimates for the three traits across ages six, nine and thirteen. For instance, 71%-77% of the BMI variance explained by the BMI-PRS can be attributed solely to the DGE. IGE estimates reached significance only for BMI measured at ages nine (Beta: 0.05, 95%CI: 0.01-0.09) and thirteen (Beta: 0.05, 95%CI: 0.01-0.09). Maternal and paternal IGE were of a similar magnitude in all our analyses. Our findings indicate that genetic nurture has limited influence on anthropometric traits during formative years. In addition, we do not observe differences between the maternal and paternal indirect contributions to these traits, opposite to the stronger maternal nurturing effect reported for other traits.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1744-1752"},"PeriodicalIF":3.2,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12498280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144951917","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}

引用次数: 0

Sleep in a mouse model of fragile X syndrome is resistant to metabolic manipulations. 脆性X综合征小鼠模型的睡眠抵抗代谢操纵。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-10-02 DOI: 10.1093/hmg/ddaf149

Mariela Lopez Valencia, Ricardo A Velázquez Aponte, Joseph A Baur, Thomas A Jongens, Amita Sehgal

{"title":"Sleep in a mouse model of fragile X syndrome is resistant to metabolic manipulations.","authors":"Mariela Lopez Valencia, Ricardo A Velázquez Aponte, Joseph A Baur, Thomas A Jongens, Amita Sehgal","doi":"10.1093/hmg/ddaf149","DOIUrl":"https://doi.org/10.1093/hmg/ddaf149","url":null,"abstract":"Fragile X Syndrome is the most prevalent known genetic cause of intellectual disability (ID), affecting around 1 in 4 000 individuals, and is also highly associated with autism spectrum disorder (ASD). Humans with the disorder and animal models display sleep and metabolic abnormalities. Given growing evidence of links between sleep and metabolism, we sought to determine if metabolic abnormalities underlie sleep deficits in mice lacking the Fragile X messenger ribonucleoprotein 1 (FMR1) gene. We found that metformin, a drug that targets metabolic pathways and has been shown to alleviate other symptoms in FXS, did not rescue sleep in mutant mice. Instead, metformin enhanced activity of Fmr1 knockout (KO) mice. As a way of exaggerating possible metabolic phenotypes, we treated mice with a high fat diet (HFD) and found that although this disrupted the sleep pattern in controls, it did not impact the sleep phenotype in Fmr1 KOs. Increased sleep during the dark phase, caused by HFD in wild type animals, was alleviated by metformin treatment. Metformin also decreased weight gain of wild type animals on a HFD, but the effect was delayed in Fmr1 KO mice. Fmr1 KO mice with or without metformin treatment displayed hyperphagia on a HFD, yet did not show higher weight gain than wild type. And, surprisingly, their glucose tolerance was equivalent to that of wild type mice on metformin. We suggest that Fmr1 KO mice are better able to metabolize fat and so are relatively resistant to its negative effects on sleep and metabolism.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212521","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}

引用次数: 0

N-Lactoyl amino acids: insights from metabolite genome-wide association studies and phenome-wide association analysis. n -乳酰氨基酸：来自代谢物全基因组关联研究和全表型关联分析的见解。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-09-28 DOI: 10.1093/hmg/ddaf152

Asma A Elashi, Aleem Razzaq, Najeha Anwardeen, Khaled Naja, Mashael Alshafai, Ilhame Diboun, Omar Albagha, Mohamed A Elrayess

{"title":"N-Lactoyl amino acids: insights from metabolite genome-wide association studies and phenome-wide association analysis.","authors":"Asma A Elashi, Aleem Razzaq, Najeha Anwardeen, Khaled Naja, Mashael Alshafai, Ilhame Diboun, Omar Albagha, Mohamed A Elrayess","doi":"10.1093/hmg/ddaf152","DOIUrl":"https://doi.org/10.1093/hmg/ddaf152","url":null,"abstract":"N-lactoyl-amino acids (Lac-AA) are emerging as important metabolites with diverse physiological roles. This study integrates metabolomics and genomics to investigate the genetic determinants and clinical relevance of three Lac-AA: N-Lactoyl phenylalanine (Lac-Phe), N-Lactoyl tyrosine (Lac-Tyr), and N-Lactoyl valine (Lac-Tyr). We conducted a metabolome-wide association study (mGWAS) on 2811 participants followed by a phenome-wide association study (PheWAS) and pathway enrichment analysis. Our mGWAS revealed modest genetic contributions to Lac-AA levels, with genome-wide significant loci identified for Lac-Tyr and Lac-Val, but not for Lac-Phe. PheWAS analysis linked these genetic variants to key clinical traits, including white blood cell count, platelet count, and glucose levels. Pathway enrichment highlighted the involvement of Lac-AA in immune-metabolic crosstalk, particularly in inflammation and energy metabolism. These findings suggest that Lac-AA levels are primarily influenced by dynamic metabolic or inflammatory states rather than fixed genetic factors. Our results underscore the potential of Lac-AA as metabolic sensors and biomarkers at the intersection of cellular energy states and systemic inflammation, opening new avenues for research in metabolic and inflammatory disorders.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185771","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}

引用次数: 0

Breast cancer genetic testing uptake in the Midwest, USA: a systematic review of barriers and facilitators among minority populations. 美国中西部地区乳腺癌基因检测的采用：对少数民族人群中障碍和促进因素的系统回顾。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-09-25 DOI: 10.1093/hmg/ddaf139

Nandu Meshram, Bobie Williams, Abigail Andresen, Dominic Mosha, Melissa Vetter

{"title":"Breast cancer genetic testing uptake in the Midwest, USA: a systematic review of barriers and facilitators among minority populations.","authors":"Nandu Meshram, Bobie Williams, Abigail Andresen, Dominic Mosha, Melissa Vetter","doi":"10.1093/hmg/ddaf139","DOIUrl":"https://doi.org/10.1093/hmg/ddaf139","url":null,"abstract":"Background: Hereditary breast cancer, primarily linked to pathogenic BRCA1 and BRCA2 mutations, accounts for 5%-10% of all breast cancer cases in the United States. Despite national guidelines recommending genetic testing for individuals at elevated hereditary risk, uptake remains disproportionately low among African American and Hispanic/Latina women. Despite elevated risk in Black women data on genetic testing uptake in St. Louis is absent.Objective: This systematic review aimed to address three research questions: (1) Are there racial and ethnic disparities in the utilization of BRCA genetic testing in Saint Louis? (2) What individual, provider, and systemic factors influence testing uptake among diverse populations? (3) What policy-level interventions are feasible and effective to improve BRCA testing rates in the city?Methods: A systematic search of MEDLINE, EMBASE, APA PsycInfo, CINAHL Plus, Scopus, and Web of Science yielded 264 unique records. Twenty-five peer-reviewed studies published between 1996 and 2024 were included after applying inclusion criteria and quality appraisal. The studies span quantitative, qualitative, and mixed methods research on high-risk populations.Results: BRCA awareness among African American women was significantly lower (12%-32%) than among White women (65%-75%). Fear of results (54%), mistrust, and concern over genetic discrimination (60%) were major barriers. Referral disparities were also stark-African American women were 50% less likely to receive provider referrals. Only 5% of genetic counselors identified as Black or Hispanic.Conclusions: No studies specifically examined BRCA testing disparities in Saint Louis. Findings from similar Midwestern cities suggest urgent need for locally informed, equity-focused interventions.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136866","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}

引用次数: 0

Haploinsufficiency of Runx2 restores the cranial sutures in a mouse model of Pdgfrb-related craniosynostosis. 在pdgfrb相关颅缝闭锁小鼠模型中，Runx2单倍不足恢复颅缝。

IF 3.2 2区生物学

Human molecular genetics Pub Date : 2025-09-25 DOI: 10.1093/hmg/ddaf148

Eri Ogawa, Tomona Oikawa, Shinya Ayabe, Tomoru Miwa, Seiya Mizuno, Taiki Nozaki, Kenjiro Kosaki, Atsushi Yoshiki, Masaru Tamura, Toshiki Takenouchi

{"title":"Haploinsufficiency of Runx2 restores the cranial sutures in a mouse model of Pdgfrb-related craniosynostosis.","authors":"Eri Ogawa, Tomona Oikawa, Shinya Ayabe, Tomoru Miwa, Seiya Mizuno, Taiki Nozaki, Kenjiro Kosaki, Atsushi Yoshiki, Masaru Tamura, Toshiki Takenouchi","doi":"10.1093/hmg/ddaf148","DOIUrl":"https://doi.org/10.1093/hmg/ddaf148","url":null,"abstract":"Syndromic forms of craniosynostosis occur as a result of dysregulation of various molecular signaling cascades. In humans, a specific gain-of-function mutation (W566R) in PDGFRB causes a distinctive overgrowth syndrome (OMIM # 616592). Affected individuals exhibit distinctive facial features and craniosynostosis. Using CRISPR/Cas9 gene editing, we generated a mouse model carrying the same pathogenic variant of PDGFRB. The Pdgfrb+/W565R mice exhibited craniosynostosis with skull-base malformation: thus, we successfully recapitulated the human disease phenotype. In humans, haploinsufficiency of RUNX2, a critical transcription factor in osteogenesis, results in defects of the skull and clavicles due to insufficient membranous ossification. Such phenotypes have been well reproduced in Runx2+/- mice. To delineate the molecular mechanisms underlying the development of Pdgfrb-related craniosynostosis, we crossed the Pdgfrb+/W565R mice with Runx2+/- mice. It is noteworthy that the double- mutant mice, i.e. Pdgfrb+/W565R Runx2+/- mice, exhibited near complete restoration of the cranial sutures and skull base. The present observation provides in vivo evidence that overactivation of Pdgfrb signaling leads to craniosynostosis through the effect of Runx2. The phenotypic reversal of the cranial structures suggests that modification of the Pdgfrb-Runx2 signaling cascade might offer a novel therapeutic opportunity for craniosynostosis.","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149001","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}

引用次数: 0