Adult Endocrinology and Diabetes, Jazan Endocrinology & Diabetes Center, Ministry of Health, Jazan 82723, Saudi Arabia.
Endocrinology Department, Faculty of Medicine and Health Sciences, Taiz University, Taiz 11712, Yemen.
Int J Mol Sci. 2024 Nov 10;25(22):12060. doi: 10.3390/ijms252212060.
Familial partial lipodystrophies (FPLDs) are very rare inherited disorders characterized by partial loss of adipose tissue from the upper and lower extremities. At least seven subtypes of FPLD have been identified and are mostly dominantly inherited. FPLD type 3 is caused by mutations in the PPARγ gene, which encodes for the protein peroxisome proliferator-activated receptor gamma (PPARγ). We identified a Saudi female with PFLD3 presented with partial lipoatrophy, uncontrolled diabetes, severe hypertriglyceridemia, and recurrent pancreatitis. The clinical and biochemical findings in this proband were described before and after treatment with Pioglitazone in addition to the conventional treatment. DNA extraction and whole exome sequencing (WES) were performed to detect the variant. The mutant gene was subjected to Sanger analysis to confirm the results. We applied five specific computational prediction tools to assess the pathogenicity of variation, namely the MT, DANN, CADD, BayesDel, and fitCons tools. We assessed protein modeling and stability with the AlphaFold-generated structures for both wild-type and mutant proteins. Finally, we conducted molecular docking using the AutoDock Vina virtual docking. Upon whole exome sequencing, a missense mutation was detected in the PPARγ gene associated with FPLD3. This variant is a novel mutation that has not been described in all genome databases. Sanger analysis confirmed the heterogenicity and pathogenicity of this variant. All five computational prediction tools indicate that this variant is considered highly pathogenic. Our patient showed a dramatic response to Pioglitazone, a synthetic PPARγ agonist. From structural modeling, we found that the enhanced binding affinity of the mutant PPARγ protein to Pioglitazone likely improves the activation of PPARγ, enhancing its transcriptional activity and resulting in better clinical outcomes. These findings extend the spectrum of PPARγ mutations responsible for FPLD3 and highlight the potential for personalized treatment strategies based on genetic mutations.
家族性部分脂肪营养不良症（FPLD）是一种非常罕见的遗传性疾病，其特征是上肢和下肢的部分脂肪组织缺失。至少已经确定了七种 FPLD 亚型，且大多为显性遗传。FPLD 3 型是由 PPARγ 基因突变引起的，该基因编码过氧化物酶体增殖物激活受体γ（PPARγ）蛋白。我们鉴定了一位沙特女性 FPLD3 患者，表现为部分脂肪萎缩、糖尿病失控、严重高甘油三酯血症和反复发作的胰腺炎。在本研究中，我们描述了该先证者在接受吡格列酮治疗（除常规治疗外）前后的临床和生化发现。进行 DNA 提取和全外显子组测序（WES）以检测变异。对突变基因进行 Sanger 分析以确认结果。我们应用了五个特定的计算预测工具来评估变异的致病性，即 MT、DANN、CADD、BayesDel 和 fitCons 工具。我们使用 AlphaFold 生成的野生型和突变型蛋白质结构评估蛋白质建模和稳定性。最后，我们使用 AutoDock Vina 虚拟对接进行分子对接。全外显子组测序检测到 PPARγ 基因与 FPLD3 相关的错义突变。该变体是一种新的突变，尚未在所有基因组数据库中描述。Sanger 分析证实了该变体的异质性和致病性。所有五个计算预测工具均表明，该变体被认为具有高度致病性。我们的患者对吡格列酮表现出显著的反应，吡格列酮是一种合成的 PPARγ 激动剂。从结构建模中，我们发现突变型 PPARγ 蛋白与吡格列酮的结合亲和力增强可能改善 PPARγ 的激活，增强其转录活性，从而带来更好的临床结果。这些发现扩展了导致 FPLD3 的 PPARγ 突变谱，并强调了基于遗传突变的个性化治疗策略的潜力。
