Molecular study and structural modeling of a variant in the GDF15 gene in the context of severe obesity

IF 0.3 Q4 NUTRITION & DIETETICS

CAHIERS DE NUTRITION ET DE DIETETIQUE Pub Date : 2026-08-01 Epub Date: 2026-09-24 DOI:10.1016/j.cnd.2026.08.095

Laura Wendling Gouvêa, Izadora Stephanie da Silva Assis, Ritiele Bastos De Souza, Lohanna Palhinha, Kaio Cezar Rodrigues Salum, Tamara Silva, Mário Campos Júnior, João Régis Ivar Carneiro, Patrícia Torres Bozza, Verônica Marques Zembrzuski, Ana Carolina Proença Da Fonseca

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Based on the conserved location of residue 211 at the cysteine knot of the protein, structure that confers its stability, this variant was predicted to be potentially pathogenic. Molecular modeling step was performed using Protein Data Bank 5VZ3 file in the UCSF Chimera X software, and priority was given to the study of the GDF15 rs372120002 variant. Analysis of the modeled mutant structure indicated that the cysteine residue at position 211 forms an intrasubunit disulfide bridge with the cysteine residue at position 274 in the mature domain of GDF-15, which is maintained by the thiol group present in the cysteine residue. As a result of the replacement of the residue with glycine, the disulfide bond is broken, altering the conformational stability of the protein, which suggests a possible impairment in the folding and secretion of GDF-15. 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As a result of the replacement of the residue with glycine, the disulfide bond is broken, altering the conformational stability of the protein, which suggests a possible impairment in the folding and secretion of GDF-15. Interestingly, serum GDF-15 levels in the individual carrying this genetic variant was 191.84pg/mL, below the reference range of 200–1,200pg/mL.</div><div><h3>Conclusion</h3><div>These findings contribute to the characterization of the GDF15 profile in a Brazilian population and suggest that the presence of GDF15 rs372120002 variant may induce structural changes in protein through disruption of a disulfide bond within the cystine knot. 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引用次数: 0

Abstract

Background/objective

Elucidation of the genetic component in obesity is supported by the presence of variations in genes associated with energy homeostasis. Because it encodes a protein that reduces appetite and leads to weight loss, the growth differentiation factor 15 (GDF15) gene is of interest for investigation in obesity. In this context, the present study aimed to screen the coding region of GDF15 in patients with severe early-onset obesity and perform molecular modeling of rare variants identified as potentially pathogenic.

Methods

Following approval by the ethic committee (HUCFF/UFRJ CAAE No. 69137623.2.0000.5257) the GDF15 coding region was analyzed in 103 participants after DNA extraction, using automated Sanger sequencing.

Results

A total of 17 variants were identified, and among these, through in silico analyses, the non-synonymous GDF15 rs372120002 [p.(Cys211Gly)] variant is particularly noteworthy. Based on the conserved location of residue 211 at the cysteine knot of the protein, structure that confers its stability, this variant was predicted to be potentially pathogenic. Molecular modeling step was performed using Protein Data Bank 5VZ3 file in the UCSF Chimera X software, and priority was given to the study of the GDF15 rs372120002 variant. Analysis of the modeled mutant structure indicated that the cysteine residue at position 211 forms an intrasubunit disulfide bridge with the cysteine residue at position 274 in the mature domain of GDF-15, which is maintained by the thiol group present in the cysteine residue. As a result of the replacement of the residue with glycine, the disulfide bond is broken, altering the conformational stability of the protein, which suggests a possible impairment in the folding and secretion of GDF-15. Interestingly, serum GDF-15 levels in the individual carrying this genetic variant was 191.84 pg/mL, below the reference range of 200–1,200 pg/mL.

Conclusion

These findings contribute to the characterization of the GDF15 profile in a Brazilian population and suggest that the presence of GDF15 rs372120002 variant may induce structural changes in protein through disruption of a disulfide bond within the cystine knot. Therefore, this variant represents a relevant target for functional studies and molecular dynamics analyses.

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严重肥胖背景下GDF15基因变异的分子研究和结构建模

背景/目的与能量稳态相关的基因变异的存在支持了肥胖遗传成分的阐明。由于生长分化因子15 （GDF15）基因编码一种降低食欲并导致体重减轻的蛋白质，因此对肥胖的研究很感兴趣。在此背景下，本研究旨在筛选严重早发性肥胖患者的GDF15编码区，并对鉴定为潜在致病性的罕见变异进行分子建模。与能量稳态相关的基因变异的存在支持了肥胖遗传成分的阐明。由于生长分化因子15 （GDF15）基因编码一种降低食欲并导致体重减轻的蛋白质，因此对肥胖的研究很感兴趣。在此背景下，本研究旨在筛选严重早发性肥胖患者的GDF15编码区，并对鉴定为潜在致病性的罕见变异进行分子建模。方法经伦理委员会批准（huff /UFRJ CAAE No. 69137623.2.0000.5257），对103名受试者DNA提取后的GDF15编码区进行自动Sanger测序分析。经伦理委员会批准（HUCFF/UFRJ CAAE No. 69137623.2.0000.5257），对103名受试者进行DNA提取后的GDF15编码区分析，采用自动Sanger测序。结果共鉴定出17个变异，其中，通过计算机分析，非同义的GDF15 rs372120002 [p。[Cys211Gly]变体是特别值得注意的。基于该蛋白半胱氨酸结处211残基的保守位置，该结构赋予其稳定性，该变异被预测为具有潜在致病性。利用UCSF Chimera X软件中的Protein Data Bank 5VZ3文件进行分子建模步骤，优先研究GDF15 rs372120002变异。对模型突变体结构的分析表明，在GDF-15的成熟结构域中，211位的半胱氨酸残基与274位的半胱氨酸残基形成亚基内二硫桥，由半胱氨酸残基中的巯基维持。由于残基被甘氨酸取代，二硫键被破坏，改变了蛋白质的构象稳定性，这表明GDF-15的折叠和分泌可能受到损害。有趣的是，携带该基因变体的个体血清GDF-15水平为191.84 pg/mL，低于200 - 1200 pg/mL的参考范围。共鉴定了17个变体，其中，通过计算机分析，非同义GDF15 rs372120002 [p. 11]。[Cys211Gly]变体是特别值得注意的。基于该蛋白半胱氨酸结处211残基的保守位置，该结构赋予其稳定性，该变异被预测为具有潜在致病性。利用UCSF Chimera X软件中的Protein Data Bank 5VZ3文件进行分子建模步骤，优先研究GDF15 rs372120002变异。对模型突变体结构的分析表明，在GDF-15的成熟结构域中，211位的半胱氨酸残基与274位的半胱氨酸残基形成亚基内二硫桥，由半胱氨酸残基中的巯基维持。由于残基被甘氨酸取代，二硫键被破坏，改变了蛋白质的构象稳定性，这表明GDF-15的折叠和分泌可能受到损害。有趣的是，携带该基因变体的个体血清GDF-15水平为191.84 pg/mL，低于200 - 1200 pg/mL的参考范围。这些发现有助于描述巴西人群中GDF15的特征，并表明GDF15 rs372120002变体的存在可能通过破坏胱氨酸结内的二硫键来诱导蛋白质的结构变化。因此，这种变异代表了功能研究和分子动力学分析的相关目标。这些发现有助于描述巴西人群中GDF15的特征，并表明GDF15 rs372120002变体的存在可能通过破坏胱氨酸结内的二硫键来诱导蛋白质的结构变化。因此，这种变异代表了功能研究和分子动力学分析的相关目标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CAHIERS DE NUTRITION ET DE DIETETIQUE NUTRITION & DIETETICS-

CiteScore

0.60

自引率

33.30%

发文量

审稿时长

65 days

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