Nurana Mammadova, A Baki Yildirim, Nihal Hatipoglu, Munis Dundar
{"title":"First Report of a Novel Pathogenic Variant in the RREB1 Gene Associated With Obesity and Metabolic Syndrome.","authors":"Nurana Mammadova, A Baki Yildirim, Nihal Hatipoglu, Munis Dundar","doi":"10.1111/cge.70001","DOIUrl":null,"url":null,"abstract":"<p><p>Ras-responsive element binding protein 1 (RREB1) is a zinc finger transcription factor that is crucial in regulating cell growth, gene expression, and DNA repair. It functions as both a repressor and an activator, with its activity controlled by the MAPK signaling pathway. RREB1 has been implicated in various conditions such as type 2 diabetes (T2D), obesity, and cancer, suggesting its potential as both a biomarker and a therapeutic target for these diseases. While several cases of 6p terminal deletions in the RREB1 gene and one case of Noonan-like RASopathy due to a loss-of-function variant have been reported, this study presents the first case of a pathogenic loss-of-function variant in RREB1 associated with morbid obesity and metabolic disturbances. Our patient, a 16-year-old male, exhibited morbid obesity, metabolic disorders, moderate intellectual disability, and atypical autism symptoms. He was referred to our clinic by the pediatric endocrinology department for genetic evaluation. Initial genetic testing included karyotype analysis and SNP array testing with 700 000 probes. Whole exome sequencing (WES) was then performed on the patient and his family, revealing a de novo novel variant, c.3178_3179del, p.(Glu1060Argfs*37) in the RREB1 gene, which was confirmed by Sanger sequencing. This novel variant underscores the critical role of RREB1 in regulating metabolic processes, particularly obesity. Additionally, the patient's neurodevelopmental delay aligns with previously reported findings of RREB1 loss-of-function variants. These results highlight the need for further research to fully understand the metabolic implications of RREB1 gene loss, with this study providing valuable insights for future investigations.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":" ","pages":""},"PeriodicalIF":2.3000,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Genetics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1111/cge.70001","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Ras-responsive element binding protein 1 (RREB1) is a zinc finger transcription factor that is crucial in regulating cell growth, gene expression, and DNA repair. It functions as both a repressor and an activator, with its activity controlled by the MAPK signaling pathway. RREB1 has been implicated in various conditions such as type 2 diabetes (T2D), obesity, and cancer, suggesting its potential as both a biomarker and a therapeutic target for these diseases. While several cases of 6p terminal deletions in the RREB1 gene and one case of Noonan-like RASopathy due to a loss-of-function variant have been reported, this study presents the first case of a pathogenic loss-of-function variant in RREB1 associated with morbid obesity and metabolic disturbances. Our patient, a 16-year-old male, exhibited morbid obesity, metabolic disorders, moderate intellectual disability, and atypical autism symptoms. He was referred to our clinic by the pediatric endocrinology department for genetic evaluation. Initial genetic testing included karyotype analysis and SNP array testing with 700 000 probes. Whole exome sequencing (WES) was then performed on the patient and his family, revealing a de novo novel variant, c.3178_3179del, p.(Glu1060Argfs*37) in the RREB1 gene, which was confirmed by Sanger sequencing. This novel variant underscores the critical role of RREB1 in regulating metabolic processes, particularly obesity. Additionally, the patient's neurodevelopmental delay aligns with previously reported findings of RREB1 loss-of-function variants. These results highlight the need for further research to fully understand the metabolic implications of RREB1 gene loss, with this study providing valuable insights for future investigations.
Ras-responsive element binding protein 1 (RREB1)是一种锌指转录因子,在调节细胞生长、基因表达和DNA修复中起重要作用。它既是抑制因子又是激活因子,其活性受MAPK信号通路控制。RREB1与2型糖尿病(T2D)、肥胖和癌症等多种疾病有关,表明其作为这些疾病的生物标志物和治疗靶点的潜力。虽然已经报道了几例RREB1基因6p末端缺失和一例noonan样RASopathy(由于功能丧失变体),但本研究首次报道了与病态肥胖和代谢紊乱相关的RREB1致病性功能丧失变体。我们的患者是一名16岁的男性,表现出病态肥胖、代谢紊乱、中度智力残疾和非典型自闭症症状。他是由儿科内分泌科转介到我们诊所进行基因评估的。初步基因检测包括核型分析和SNP阵列检测,共70万个探针。然后对患者及其家人进行全外显子组测序(WES),发现RREB1基因中有一个全新的变异,c.3178_3179del, p.(Glu1060Argfs*37),经Sanger测序证实。这种新的变异强调了RREB1在调节代谢过程,特别是肥胖中的关键作用。此外,患者的神经发育迟缓与先前报道的RREB1功能丧失变体的发现一致。这些结果强调需要进一步研究以充分了解RREB1基因丢失对代谢的影响,本研究为未来的研究提供了有价值的见解。
期刊介绍:
Clinical Genetics links research to the clinic, translating advances in our understanding of the molecular basis of genetic disease for the practising clinical geneticist. The journal publishes high quality research papers, short reports, reviews and mini-reviews that connect medical genetics research with clinical practice.
Topics of particular interest are:
• Linking genetic variations to disease
• Genome rearrangements and disease
• Epigenetics and disease
• The translation of genotype to phenotype
• Genetics of complex disease
• Management/intervention of genetic diseases
• Novel therapies for genetic diseases
• Developmental biology, as it relates to clinical genetics
• Social science research on the psychological and behavioural aspects of living with or being at risk of genetic disease