Laboratório de Genética Molecular do Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo, São Paulo, Brazil.
PLoS One. 2010 Nov 30;5(11):e14136. doi: 10.1371/journal.pone.0014136.
Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.
马凡综合征是一种常染色体显性遗传的结缔组织疾病，由原纤维蛋白 1 编码基因 FBN1 的突变引起。患者表现出心血管、眼部和骨骼的表现，尽管完全外显，但 MFS 的特征是在个体内和个体间存在广泛的临床变异性。在这里，我们描述了一种新的 MFS 小鼠模型，该模型重现了人类综合征的临床异质性。携带与 mgΔ 小鼠模型相同的 19-24 号外显子内部缺失的突变型 Fbn1 等位基因 mgΔloxPneo 的杂合子，表现出微纤维沉积缺陷、肺气肿、主动脉壁恶化和脊柱后凸。然而，在 129/Sv 背景下，临床表型的发病时间早于 C57BL/6 背景，这表明这两种小鼠品系之间存在 MFS 的遗传修饰因子。此外，我们在 129/Sv 同源杂合子中描述了广泛的临床变异性，表明表观遗传因素参与了疾病的严重程度。最后，我们显示 Fbn1 表达水平与表型严重程度之间存在强烈的负相关，这证实了正常原纤维蛋白 1 在 MFS 发病机制中的保护作用，并支持基于增加 Fbn1 表达的治疗方法的发展。
