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Abstract：
OBJECTIVE: Type 3 Familial Partial Lipodystrophy (FPLD3) is a rare metabolic disease related to pathogenic PPARG gene variants. FPLD3 is characterized by a loss of fatty tissue in the upper and lower limbs, hips, and face. FPLD3 pathophysiology is usually associated with metabolic comorbidities such as type 2 diabetes, insulin resistance, hypertriglyceridemia, and liver dysfunction. Here, we clinically and molecularly characterized FPLD3 patients harboring novel PPARG pathogenic variants.
METHODS: Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins.
RESULTS: We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein.
CONCLUSIONS: Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.
METHODS: Lipodystrophy-suspected patients were recruited by clinicians from an Endocrinology Reference Center. Clinical evaluation was performed, biological samples were collected for biochemical analysis, and DNA sequencing was performed to define the pathogenic variants associated with the lipodystrophic phenotype found in our clinically diagnosed FPLD subjects. Bioinformatics predictions were conducted to characterize the novel mutated PPARγ proteins.
RESULTS: We clinically described FPLD patients harboring two novel heterozygous PPARG variants in Brazil. Case 1 had the c.533T > C variant, which promotes the substitution of leucine to proline in position 178 (p.Leu178Pro), and cases 2 and 3 had the c.641 C > T variant, which results in the substitution of proline to leucine in the position 214 (p.Pro214Leu) at the PPARγ2 protein. These variants result in substantial conformational changes in the PPARγ2 protein.
CONCLUSIONS: Two novel PPARG pathogenic variants related to FPLD3 were identified in a Brazilian FPLD cohort. These data will provide new epidemiologic data concerning FPLD3 and help understand the genotype-phenotype relationships related to the PPARG gene.
摘要：
目的：3型家族性部分脂肪营养不良（FPLD3）是一种与致病性PPARG基因变异有关的罕见代谢疾病。FPLD3的特征是上肢和下肢的脂肪组织损失，臀部,和脸。FPLD3病理生理学通常与代谢合并症相关，如2型糖尿病，胰岛素抵抗，高甘油三酯血症,和肝功能障碍。这里,我们对具有新型PPARG致病变种的FPLD3患者进行了临床和分子表征.
方法：临床医生从内分泌学参考中心招募了疑似脂肪营养不良患者。进行临床评估，收集生物样本进行生化分析，并进行DNA测序以确定在我们的临床诊断的FPLD受试者中发现的与脂肪营养不良表型相关的致病变异。进行生物信息学预测以表征新的突变PPARγ蛋白。
结果：我们在巴西临床描述了FPLD患者携带两种新的PPARG杂合变异。病例1有c.533T>C变体，促进亮氨酸在178位取代脯氨酸（p。Leu178Pro),病例2和3有c.641C>T变异，导致脯氨酸在214位被亮氨酸取代（p。Pro214Leu）在PPARγ2蛋白上。这些变体导致PPARγ2蛋白的实质性构象变化。
结论：在巴西FPLD队列中发现了两种与FPLD3相关的新型PPARG致病变异。这些数据将提供有关FPLD3的新流行病学数据，并有助于了解与PPARG基因相关的基因型-表型关系。
方法：临床医生从内分泌学参考中心招募了疑似脂肪营养不良患者。进行临床评估，收集生物样本进行生化分析，并进行DNA测序以确定在我们的临床诊断的FPLD受试者中发现的与脂肪营养不良表型相关的致病变异。进行生物信息学预测以表征新的突变PPARγ蛋白。
结果：我们在巴西临床描述了FPLD患者携带两种新的PPARG杂合变异。病例1有c.533T>C变体，促进亮氨酸在178位取代脯氨酸（p。Leu178Pro),病例2和3有c.641C>T变异，导致脯氨酸在214位被亮氨酸取代（p。Pro214Leu）在PPARγ2蛋白上。这些变体导致PPARγ2蛋白的实质性构象变化。
结论：在巴西FPLD队列中发现了两种与FPLD3相关的新型PPARG致病变异。这些数据将提供有关FPLD3的新流行病学数据，并有助于了解与PPARG基因相关的基因型-表型关系。
