Genetic and functional analyses of CTBP2 in anorexia nervosa and body weight regulation

IF 9.6 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Psychiatry Pub Date : 2024-11-07 DOI:10.1038/s41380-024-02791-3
Johanna Giuranna, Yiran Zheng, Matthäus Brandt, Sigrid Jall, Amrita Mukherjee, Soni Shankhwar, Simone Renner, Nirup Kumar Kurapati, Caroline May, Triinu Peters, Beate Herpertz-Dahlmann, Jochen Seitz, Martina de Zwaan, Wolfgang Herzog, Stefan Ehrlich, Stephan Zipfel, Katrin Giel, Karin Egberts, Roland Burghardt, Manuel Föcker, Katrin Marcus, Kathy Keyvani, Timo D. Müller, Frank Schmitz, Luisa Sophie Rajcsanyi, Anke Hinney
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Abstract

The C-terminal binding protein 2 (CTBP2) gene (translational isoforms: CTBP2-L/S, RIBEYE) had been identified by a cross-trait analysis of genome-wide association studies for anorexia nervosa (AN) and body mass index (BMI). Here, we did a mutation analysis in CTBP2 by performing polymerase chain reactions with subsequent Sanger-sequencing to identify variants relevant for AN and body weight regulation and ensued functional studies. Analysis of the coding regions of CTBP2 in 462 female patients with AN (acute or recovered), 490 children and adolescents with severe obesity, 445 healthy-lean adult individuals and 168 healthy adult individuals with normal body weight detected 24 variants located in the specific exon of RIBEYE. In the initial analysis, three of these were rare non-synonymous variants (NSVs) detected heterozygously in patients with AN (p.Arg72Trp - rs146900874; p.Val289Met -rs375685611 and p.Gly362Arg - rs202010294). Four NSVs and one heterozygous frameshift variant were exclusively detected in children and adolescents with severe obesity (p.Pro53Ser - rs150867595; p.Gln175ArgfsTer45 - rs141864737; p.Leu310Val - rs769811964; p.Pro397Ala - rs76134089 and p.Pro402Ser - rs113477585). Ribeye mRNA was detected in mouse hypothalamus. No effect of fasting or overfeeding on murine hypothalamic Ribeye expression was determined. Yet, increased Ribeye expression was detected in hypothalami of leptin-treated Lepob/ob mice. This increase was not related to reduced food intake and leptin-induced weight loss. We detected rare and frequent variants in the RIBEYE specific exon in both patients with AN and in children and adolescents with severe obesity. Our data suggest RIBEYE as a relevant gene for weight regulation.

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CTBP2 在神经性厌食症和体重调节中的遗传和功能分析
通过对神经性厌食症(AN)和体重指数(BMI)的全基因组关联研究进行交叉分析,发现了C端结合蛋白2(CTBP2)基因(翻译异构体:CTBP2-L/S,RIBEYE)。在此,我们通过聚合酶链式反应和随后的桑格测序对 CTBP2 进行了突变分析,以确定与神经性厌食症和体重调节相关的变异,并进行随后的功能研究。对462名女性AN患者(急性或恢复期)、490名严重肥胖的儿童和青少年、445名健康的瘦成年人和168名体重正常的健康成年人的CTBP2编码区进行分析,发现了24个位于RIBEYE特定外显子上的变异。在初步分析中,其中三个是在 AN 患者中检测到的罕见非同义变异(NSV)(p.Arg72Trp - rs146900874;p.Val289Met -rs375685611 和 p.Gly362Arg - rs202010294)。在患有严重肥胖症的儿童和青少年中,只检测到 4 个 NSV 和 1 个杂合框移变异(p.Pro53Ser - rs150867595;p.Gln175ArgfsTer45 - rs141864737;p.Leu310Val - rs769811964;p.Pro397Ala - rs76134089 和 p.Pro402Ser - rs113477585)。在小鼠下丘脑中检测到了肋眼 mRNA。禁食或过量进食对小鼠下丘脑核眼表达没有影响。然而,在经瘦素处理的Lepob/ob小鼠下丘脑中检测到肋眼表达增加。这种增加与食物摄入量减少和瘦素诱导的体重减轻无关。我们在自闭症患者以及严重肥胖的儿童和青少年中都检测到了 RIBEYE 特异外显子的罕见和频繁变异。我们的数据表明,RIBEYE 是一个与体重调节相关的基因。
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来源期刊
Molecular Psychiatry
Molecular Psychiatry 医学-精神病学
CiteScore
20.50
自引率
4.50%
发文量
459
审稿时长
4-8 weeks
期刊介绍: Molecular Psychiatry focuses on publishing research that aims to uncover the biological mechanisms behind psychiatric disorders and their treatment. The journal emphasizes studies that bridge pre-clinical and clinical research, covering cellular, molecular, integrative, clinical, imaging, and psychopharmacology levels.
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