Journal of Human Genetics最新文献

Further delineation of KIDAR syndrome: Two new cases with novel variants, functional analysis of the variants and a comprehensive review. 进一步描述KIDAR综合征：两个新病例的新变体，变体的功能分析和全面回顾。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-04-24 DOI: 10.1038/s10038-026-01476-9

Şule Altıner, Ezgi Gökpınar İli, Ahmet Karer Yurtdaş, Okan Kurtçu, Neslihan Doğulu, Ayşe Öktem, Engin Köse, Fatma Tuba Eminoğlu, Behiye Tuğçe Yıldırım, Ayça Dilruba Aslanger, Gözde Yeşil Sayın, Halil Gürhan Karabulut

{"title":"Further delineation of KIDAR syndrome: Two new cases with novel variants, functional analysis of the variants and a comprehensive review.","authors":"Şule Altıner, Ezgi Gökpınar İli, Ahmet Karer Yurtdaş, Okan Kurtçu, Neslihan Doğulu, Ayşe Öktem, Engin Köse, Fatma Tuba Eminoğlu, Behiye Tuğçe Yıldırım, Ayça Dilruba Aslanger, Gözde Yeşil Sayın, Halil Gürhan Karabulut","doi":"10.1038/s10038-026-01476-9","DOIUrl":"https://doi.org/10.1038/s10038-026-01476-9","url":null,"abstract":"The syndrome known as KIDAR (keratitis, ichthyosis, deafness, autosomal recessive) is extremely rare. It is caused by biallelic mutations in AP1B1, encoding adaptor-related protein complex, beta-1 subunit. AP1 complex takes part in the formation of vesicles and the selection of cargo proteins in the trans-golgi network. It also contributes to vesicular transport of ATP7A and ATP7B. Accordingly, KIDAR has been defined as both an adaptinopathy and a copper metabolism disorder. Eleven cases have been reported to date. We report two new KIDAR cases with novel splice site variants-c.1796+1 G > T and c.1796+1 G > C-in AP1B1 (NM_001127.4) gene. Functional analysis of the first variant revealed that this mutation disrupts the normal splicing process, resulting in the creation of a cryptic donor site 150 base pairs downstream of the canonical donor site which introduces a premature stop codon into the transcript. We also present a review of previously reported KIDAR cases and genetic disorders involving altering copper metabolism and highlight our patients' new clinical features, which may broaden the recognized phenotype. A detailed study of these cases may contribute to the ongoing genetic and clinical characterization of KIDAR syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147773681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Associations of polygenic risk scores for type 2 diabetes with metabolic measures in Pacific Islanders from Guam and Saipan. 关岛和塞班岛太平洋岛民2型糖尿病多基因风险评分与代谢指标的关系

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-04-09 DOI: 10.1038/s10038-026-01474-x

Maria J Ramirez-Luzuriaga, Saied Safabakhsh, Rasol Salehi, Sayuko Kobes, Tanisha F Aflague, Jenny Duenas Sarmiento, Joanne E Curran, Robert G Nelson, Jeffrey M Curtis, Carol D Moffett, Wen-Chi Hsueh, Robert L Hanson

{"title":"Associations of polygenic risk scores for type 2 diabetes with metabolic measures in Pacific Islanders from Guam and Saipan.","authors":"Maria J Ramirez-Luzuriaga, Saied Safabakhsh, Rasol Salehi, Sayuko Kobes, Tanisha F Aflague, Jenny Duenas Sarmiento, Joanne E Curran, Robert G Nelson, Jeffrey M Curtis, Carol D Moffett, Wen-Chi Hsueh, Robert L Hanson","doi":"10.1038/s10038-026-01474-x","DOIUrl":"https://doi.org/10.1038/s10038-026-01474-x","url":null,"abstract":"Several polygenic risk scores (PRSs) for type 2 diabetes (T2D) have been derived from genome-wide association studies (GWASs), but Pacific populations have generally not been represented in these GWASs. The aim of this study was to examine the association of PRS for T2D with diabetes and clinical measures in Pacific Islander populations from Guam and Saipan. We analyzed seven constructions of PRSs in 1990 participants in a GWAS from a community-based cross-sectional study of diabetes. Associations of T2D PRS with diabetes, maximum body mass index (BMI), fasting glucose, and HbA1c were examined with adjustment for age, sex, and the first four genetic principal components (PCs) from the GWAS (to account for population stratification). Insulin resistance/secretion measures were also analyzed in 989 participants without diabetes. All seven PRSs were strongly associated with T2D (p < 5 × 10-9 for each); a 1-SD increase in the PRS was associated with 39-81% increase in the odds of T2D (i.e., standardized odds ratio [OR] ranging 1.39-1.81) adjusting for age, sex, and PCs. We also found that a 1-SD increase in the PRS was associated with 0.30-0.46 mmol/L higher fasting glucose, and with 2.68-4.63 mmol/mol higher HbA1c adjusting for age, sex, and PCs. We found no associations of PRSs with maximum BMI or insulin measures. All seven of the T2D polygenic risk scores evaluated associated significantly and strongly with diabetes, fasting glucose and HbA1c. These analyses suggest that T2D polygenic scores, as currently derived, have a certain degree of transferability to individuals from Pacific populations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Identification and structural characterisation of a novel mutation in the CNKSR2 gene associated with Houge-Type X-Linked Intellectual Developmental Disorder. 与houge型x连锁智力发育障碍相关的CNKSR2基因新突变的鉴定和结构特征

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-04-07 DOI: 10.1038/s10038-026-01475-w

Anil Kumar, Ajay Kumar, Chandraniv Dey, Arvinder Wander, Sudip Chakraborty, Anjana Munshi

{"title":"Identification and structural characterisation of a novel mutation in the CNKSR2 gene associated with Houge-Type X-Linked Intellectual Developmental Disorder.","authors":"Anil Kumar, Ajay Kumar, Chandraniv Dey, Arvinder Wander, Sudip Chakraborty, Anjana Munshi","doi":"10.1038/s10038-026-01475-w","DOIUrl":"https://doi.org/10.1038/s10038-026-01475-w","url":null,"abstract":"Neurological disorders with overlapping phenotypes pose significant diagnostic challenges, especially the ones that occur on account of rare genetic variants. We hereby report a case of a 16-year-old male with clinical symptoms of severe intellectual disability, excessive appetite, an elongated face with decreased body weight (<-2 SD) and microcephaly (<-3 SD). Behavioral manifestations like attention deficit, hyperactivity, and impulsivity were also observed in the patient. The Exome sequencing of affected child revealed a novel frameshift insertion in the CNKSR2 gene, or connector enhancer of kinase suppressor of Ras 2, which is located on the X chromosome. In consensus with the phenotypes of the patient, this novel variant has an association with Houge type of X-linked intellectual developmental disorder. This is the first case reporting a pathogenic frameshift insertion in CNKSR2 (c.2489dup: p. Arg831Glufs *21) gene that encodes a protein that plays a significant role in neuronal proliferation, migration, and differentiation. The integrative molecular dynamics simulation analyses revealed substantial differences in the structural dynamics and stability between the wild-type protein and its mutant form, resulting in a more rigid protein due to the presence of the mutation. This finding broadens the mutation spectrum of CNKSR2 and the importance of exploring mutations in this gene in association with Intellectual developmental disorders. Early detection of such pathogenic variants in associated genes not only helps with clinical diagnosis and management but also has the potential to avert the birth of another affected individual in the family.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

SMN1 mutation spectrum and functional analysis of novel SMN1 variants in a Chinese spinal muscular atrophy cohort. 中国脊髓性肌萎缩队列中SMN1突变谱和新型SMN1变异的功能分析

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-04-07 DOI: 10.1038/s10038-026-01473-y

Gui-He Li, Li-Wen Wu, Jing Li, Sen-Wei Dong, Jing-Mei Hong, Ying-Xuan Xie, Yu-Hao Sun, Jin He, Ning Wang, Wan-Jin Chen, Hai-Zhu Chen

引用次数: 0

Rare variants in embryonic development and cell signalling genes in syndromic and non-syndromic orofacial clefts: evidence from a Colombian Caribbean cohort. 综合征型和非综合征型口面部裂中胚胎发育和细胞信号基因的罕见变异：来自哥伦比亚加勒比队列的证据。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-30 DOI: 10.1038/s10038-026-01466-x

Alejandro Silva, Carolina Jaramillo Oquendo, Jaime E Bernal, Julio Cesar Martinez, Andrew Collins, Ignacio Briceño, Escilda Benavides, Zulieth López Arrieta, Sarah Ennis

{"title":"Rare variants in embryonic development and cell signalling genes in syndromic and non-syndromic orofacial clefts: evidence from a Colombian Caribbean cohort.","authors":"Alejandro Silva, Carolina Jaramillo Oquendo, Jaime E Bernal, Julio Cesar Martinez, Andrew Collins, Ignacio Briceño, Escilda Benavides, Zulieth López Arrieta, Sarah Ennis","doi":"10.1038/s10038-026-01466-x","DOIUrl":"https://doi.org/10.1038/s10038-026-01466-x","url":null,"abstract":"Orofacial clefts (OFCs) are common craniofacial malformations broadly classified as syndromic or non-syndromic. While syndromic OFCs are often caused by rare, high-impact variants, non-syndromic OFCs are typically associated with multiple low-impact common variants. However, growing evidence suggests that rare variants may also contribute to non-syndromic OFCs. To explore this, we performed exome sequencing in 45 individuals from 20 Colombian families, predominantly from the Caribbean region, a genetically distinct and underrepresented population. Our goal was to identify rare variants potentially contributing to both syndromic and non-syndromic OFCs. We identified 15 rare protein-altering variants in 11 families that showed strong phenotype-genotype concordance. Four probands carried a previously reported common ACSS2 variant (c.1487 T > C), with two probands also harbouring variants in Pleckstrin Homology Domain Containing (PLEKH) genes. Five variants were previously reported in ClinVar (two with conflicting interpretations, one pathogenic, and two of uncertain significance), while ten were novel. Variants were found in known OFC-associated genes (MID1, FLNA, FGF10) and emerging candidates (ZFHX4, PLEKHA5, PLEKHA7). These findings provide further evidence that rare variants in developmental and signalling pathways contribute to both syndromic and non-syndromic OFCs, reinforcing previous studies and expanding the catalogue of candidate genes in underrepresented populations.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat expansions. notch3阴性cadasil疑似NOTCH2NLC GGC重复扩张患者的临床和影像学特征

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-26 DOI: 10.1038/s10038-026-01470-1

Hiraku Matsuura, Daiki Fukunaga, Ikuko Mizuta, Chisato Tamai, Rei Yasuda, Mao Mukai, Akiko Watanabe-Hosomi, Takashi Koizumi, Tomokatsu Yoshida, Tomoyuki Ohara, Takashi Kasai, Jun Sone, Toshiki Mizuno

{"title":"Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat expansions.","authors":"Hiraku Matsuura, Daiki Fukunaga, Ikuko Mizuta, Chisato Tamai, Rei Yasuda, Mao Mukai, Akiko Watanabe-Hosomi, Takashi Koizumi, Tomokatsu Yoshida, Tomoyuki Ohara, Takashi Kasai, Jun Sone, Toshiki Mizuno","doi":"10.1038/s10038-026-01470-1","DOIUrl":"https://doi.org/10.1038/s10038-026-01470-1","url":null,"abstract":"Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant inherited neurodegenerative disease caused by NOTCH2NLC GGC repeat expansions. A high-intensity signal in the corticomedullary junction (CMJ) on magnetic resonance (MR) diffusion-weighted imaging (DWI) is a well-known characteristic of NIID. However, because of its diverse clinical symptoms and frequent presence of cerebral white matter hyperintensity (WMH) lesions on MRI, patients with NIID may be suspected of having other leukoencephalopathies. The aim of the present study was to identify patients with NOTCH2NLC GGC repeat expansions among those with undiagnosed leukoencephalopathies, recruited from NOTCH3-negative cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-suspected and GFAP-negative Alexander disease (AxD)-suspected patients. Among 459 NOTCH3-negative CADASIL-suspected patients, 18 (3.9%) showed NOTCH2NLC GGC repeat expansions; however, among 40 GFAP-negative AxD-suspected patients, none exhibited such repeat expansions. On comparing 17 patients with GGC repeat expansions, whose clinical information was available, with 179 CADASIL probands previously reported by us, the former showed significantly higher frequencies of seizure (23.5 vs. 6.9%, respectively), WMH in the corpus callosum (92.9 vs. 9.2%, respectively), paravermis (21.4 vs. 2.7%, respectively), and middle cerebellar peduncle (21.4 vs. 3.4%, respectively), and DWI high-intensity signals in CMJ (61.5 vs. 1.4%, respectively). In conclusion, not only DWI high-intensity signals in CMJ, but also the WMH distribution, particularly a high frequency in the corpus callosum, and presence of seizures are useful for detecting NIID in patients with undiagnosed leukoencephalopathies.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

A novel compound heterozygous YY1AP1 variant in Grange syndrome: importance of early signs in preventing life-threatening vascular complications. Grange综合征中一种新的复合杂合YY1AP1变异：早期体征对预防危及生命的血管并发症的重要性

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-26 DOI: 10.1038/s10038-026-01471-0

Gul Unsel-Bolat, Neslihan Tezcan, Dilan Genç-Akdağ, Hamide Betül Gerik-Celebi, Alperen Tezcan, Hilmi Bolat

{"title":"A novel compound heterozygous YY1AP1 variant in Grange syndrome: importance of early signs in preventing life-threatening vascular complications.","authors":"Gul Unsel-Bolat, Neslihan Tezcan, Dilan Genç-Akdağ, Hamide Betül Gerik-Celebi, Alperen Tezcan, Hilmi Bolat","doi":"10.1038/s10038-026-01471-0","DOIUrl":"https://doi.org/10.1038/s10038-026-01471-0","url":null,"abstract":"Background: Grange syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in the YY1AP1 gene. It is clinically characterized by multisystem involvement, including vascular stenosis, brachysyndactyly, osteopenia, cardiac anomalies, and neurodevelopmental delay.Methods: Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Whole-exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis.Results: We report a 17-year-old Turkish female who presented with academic failure, speech delay, dysarthria, facial dysmorphism, and surgically corrected hand syndactyly. Notably, she exhibited no clinical signs of vascular stenosis or hypertension at the time of diagnosis. A novel compound heterozygous variant combination in YY1AP1 (NM_139119.3) was identified: c.1489_1492del (p.Glu636ProfsTer13), previously reported as pathogenic, and c.1637_1638del (p.Pro546ArgfsTer26), a novel frameshift variant. These variants were maternally and paternally inherited, respectively.Conclusion: This is the first reported case of Grange syndrome diagnosed based on neurodevelopmental and dysmorphic findings before the onset of vascular or hypertensive symptoms. Our findings highlight the importance of considering YY1AP1-related pathology in the differential diagnosis of intellectual disability and syndactyly, even in the absence of vascular features. Early genetic diagnosis enables clinical surveillance for life-threatening complications associated with this syndrome.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Genetic diagnosis of sibling cases initiated by identification of outlier gene expression using transcriptome analysis of urine-derived cells. 通过尿源性细胞转录组分析鉴定异常基因表达，对兄弟姐妹病例进行遗传诊断。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-24 DOI: 10.1038/s10038-026-01472-z

Toru Takagi, Sachiko Miyamoto, Kenji Shimizu, Yasuhiko Tanaka, Tomoko Matsubayashi, Yohei Masunaga, Hirotomo Saitsu

{"title":"Genetic diagnosis of sibling cases initiated by identification of outlier gene expression using transcriptome analysis of urine-derived cells.","authors":"Toru Takagi, Sachiko Miyamoto, Kenji Shimizu, Yasuhiko Tanaka, Tomoko Matsubayashi, Yohei Masunaga, Hirotomo Saitsu","doi":"10.1038/s10038-026-01472-z","DOIUrl":"https://doi.org/10.1038/s10038-026-01472-z","url":null,"abstract":"Transcriptome analysis can improve the diagnostic yield for neurodevelopmental disorders. We applied RNA-seq using urine-derived cells (UDCs) to a family with two affected brothers with a muscular dystrophy-dystroglycanopathy and dilated cardiomyopathy. Exome sequencing identified a maternally inherited heterozygous B3GALNT2 splice-site variant (NM_152490.5:c.261-2A>G) but no second pathogenic allele. UDCs RNA-seq with OUTRIDER detected markedly decreased expression of B3GALNT2 in the proband and a milder decrease in the father, suggesting a paternally inherited non-coding variant. Genome sequencing revealed a 357-bp heterozygous deletion encompassing the B3GALNT2 promoter and transcription start site, which segregated with the phenotype. RNA-seq supported aberrant splicing from the splice-site allele and reduction of transcripts from the deletion allele. These findings provide proof of concept that UDCs RNA-seq-guided outlier-expression analysis can identify non-coding second hits and support genetic diagnosis, and they suggest that cardiac surveillance may be warranted in B3GALNT2-related disorder as they age.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147512586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Interaction between human oxoguanine glycosylase 1 gene polymorphisms and smoking status on nasopharyngeal carcinoma risk. 人氧鸟嘌呤糖基化酶1基因多态性与吸烟状况对鼻咽癌发病的相互作用

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-23 DOI: 10.1038/s10038-026-01468-9

Fanyu Peng, Ruru Zhang, Rong Yu, Jing Wu, Lijun Wang, Yatian Liu, Delin Liu, Pengwei Yan, Baixia Yang

{"title":"Interaction between human oxoguanine glycosylase 1 gene polymorphisms and smoking status on nasopharyngeal carcinoma risk.","authors":"Fanyu Peng, Ruru Zhang, Rong Yu, Jing Wu, Lijun Wang, Yatian Liu, Delin Liu, Pengwei Yan, Baixia Yang","doi":"10.1038/s10038-026-01468-9","DOIUrl":"https://doi.org/10.1038/s10038-026-01468-9","url":null,"abstract":"This study aims to evaluate the impact of four SNPs of human 8-oxoguanine DNA glycosylase 1 (hOGG1) gene, and its interaction with smoking and alcohol drinking on the risk of nasopharyngeal carcinoma (NPC). Hardy-Weinberg equilibrium (HWE) and the relationship between four SNPs of the hOGG1 gene and the risk of NPC were tested using the SNPStats online software ( https://www.snpstats.net/start.htm ). Generalized multifactor dimensionality reduction (GMDR) was utilized to screen the optimal interaction combinations among four hOGG1 gene SNPs, smoking, and alcohol drinking. We found that rs1052133- Cys allele was associated with increased NPC risk, ORs (95% CI) were 1.42 (1.12-1.85) for Ser/Cys genotype, 1.95 (1.51-2.48) for Cys/Cys genotype, 1.57 (1.18-2.05) for Ser/Cys or Cys/Cys genotype, compared to Ser/Ser genotype. We also found that rs159153- T allele was associated with increased NPC risk, ORs (95% CI) were 1.35 (1.06-1.73) for CT genotype, 2.18 (1.62-2.85) for TT genotype, 1.45 (1.09-1.90) for CT or TT genotype, compared to CC genotype. However, we did not find any statistically significant impact of the minor alleles of rs3219008 and rs293795 on the risk of NPC. GMDR model found a significant gene-environment interaction combination (two-locus model with P = 0.018) between rs1052133 and smoking. Compared to never smokers with rs1052133 Ser/Ser genotype, ever or currently smokers with rs1052133- Ser/Cys or Cys/Cys genotype have the highest NPC risk, OR (95% CI) = 3.18 (1.94-4.42). The rs1052133 and rs159153 minor alleles, the interaction between rs1052133 and smoking, were all associated with increased NPC risk.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Allelic variation in the ATP7B gene promoter. Implications for phenotype variability, neurodegeneration and Pt resistance in tumor diseases. ATP7B基因启动子的等位基因变异。肿瘤疾病的表型变异、神经变性和铂耐药的意义。

IF 2.5 3区生物学

Journal of Human Genetics Pub Date : 2026-03-17 DOI: 10.1038/s10038-026-01469-8

Simona Incollu, Isadora Asunis, Stefania Satta, Salvatore Savasta, Georgios Loudianos

{"title":"Allelic variation in the ATP7B gene promoter. Implications for phenotype variability, neurodegeneration and Pt resistance in tumor diseases.","authors":"Simona Incollu, Isadora Asunis, Stefania Satta, Salvatore Savasta, Georgios Loudianos","doi":"10.1038/s10038-026-01469-8","DOIUrl":"https://doi.org/10.1038/s10038-026-01469-8","url":null,"abstract":"Wilson's disease (WD) is a rare genetic disorder of copper transport due to mutations in the ATP7B gene. This results in copper overload and tissue damage that is most evident in the liver and brain. Over 1000 pathogenic mutations have been found in WD patients, and of these, mutations within the ATP7B coding region predominate. In this study, we perform functional analyses of 7 rare sequence variations in the promoter region of the ATP7B gene. We performed dual luciferase reporter assays in HepG2 and SH-SY5Y cell lines under basal conditions and after the addition of 10 μM or 40 μM concentrations of CuSO4. The results showed that promoter activity varied both according to the haplotype and the cell line used. Our results suggest a potential role of promoter polymorphisms in the variation of ATP7B gene expression with probable implications in copper accumulation in the organism and consequent phenotype variation in WD. In addition, given the association of copper concentration and ATP7B expression in the brain, promoter polymorphisms could act as susceptibility determinants of neurodegeneration in the most common late-onset nervous system diseases. Finally, promoter involvement in ATP7B overexpression and platinum resistance presents new mechanisms of great importance that need to be better understood. Further experimental and clinical studies are necessary to further explore the role of the ATP7B promoter in copper and platinum management. These studies will offer new insights for the development of molecular therapies for brain degenerative and tumor diseases.","PeriodicalId":16077,"journal":{"name":"Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147473700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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