The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele
The clinical presentation of Marfan syndrome is modulated by expression of wild-type FBN1 allele
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DOI：
10.1093/hmg/ddv037
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发表时间：
2015-05-15
影响因子：
3.5
通讯作者：
Stheneur, Chantal
中科院分区：
文献类型：
--
作者：
Aubart, Melodie;Gross, Marie-Sylvie;Stheneur, Chantal
马凡综合征是一种常染色体显性遗传疾病，主要由FBN 1基因突变引起。该疾病在发病年龄或严重程度上显示出很大的变异性，并且已经证明了非常差的表型/基因型相关性。我们研究了这一假设，即表型严重程度可能与野生型（WT）等位基因合成的FBN 1（FBN 1）的可变表达水平有关。定量逆转录和聚合酶链反应被用来评估FBN 1水平的皮肤成纤维细胞从80马方患者提前终止密码子和皮肤成纤维细胞从80个控制。对照组的结果显示受试者之间FBN 1 mRNA合成水平的变化为3.9倍。在Marfan人群中发现了类似的4.4倍变异，但FBN 1 mRNA的平均水平是对照人群的一半。差异等位基因表达分析显示，超过90%的FBN 1基因转录自野生型等位基因，突变的等位基因没有被检测到。在对照人群中，独立于FBN 1的表达水平，我们观察到两个等位基因mRNA之间的稳态平衡，这表明FBN 1的表达主要取决于反式作用调节剂。最后，我们发现低水平的残留WT FBN 1 mRNA导致晶状体异位和胸畸形的高风险，并倾向于增加主动脉扩张的风险。
Marfan syndrome is an autosomal dominant disorder mainly caused by mutations within FBN1 gene. The disease displays large variability in age of onset or severity and very poor phenotype/genotype correlations have been demonstrated. We investigated the hypothesis that phenotype severity could be related to the variable expression level of fibrillin-1 (FBN1) synthesized from the wild-type (WT) allele. Quantitative reverse-transcription and polymerase chain reaction was used to evaluate FBN1 levels in skin fibroblasts from 80 Marfan patients with premature termination codons and in skin fibroblasts from 80 controls. Results in controls showed a 3.9-fold variation in FBN1 mRNA synthesis level between subjects. A similar 4.4-fold variation was found in the Marfan population, but the mean level of FBN1 mRNA was a half of the control population. Differential allelic expression analysis in Marfan fibroblasts showed that over 90% of FBN1 mRNA was transcribed from the wild allele and the mutated allele was not detected. In the control population, independently of the expression level of FBN1, we observed steady-state equilibrium between the two allelic-mRNAs suggesting that FBN1 expression mainly depends on trans-acting regulators. Finally, we show that a low level of residual WT FBN1 mRNA accounts for a high risk of ectopia lentis and pectus abnormality and tends to increase the risk of aortic dilatation.