Zetoune Almoutassem B, Fontanière Sandra, Magnin Delphine, Anczuków Olga, Buisson Monique, Zhang Chang X, Mazoyer Sylvie
Laboratoire de Génétique Moléculaire, Signalisation et Cancer UMR5201 CNRS, Equipe Labellisée par Ligue Nationale contre Cance, Université Lyon 1, Université de Lyon, Faculté de Médecine, Lyon, France.
BMC Genet. 2008 Dec 5;9:83. doi: 10.1186/1471-2156-9-83.
The Nonsense-Mediated mRNA Decay (NMD) pathway detects and degrades mRNAs containing premature termination codons, thereby preventing the accumulation of potentially detrimental truncated proteins. Intertissue variation in the efficiency of this mechanism has been suggested, which could have important implications for the understanding of genotype-phenotype correlations in various genetic disorders. However, compelling evidence in favour of this hypothesis is lacking. Here, we have explored this question by measuring the ratio of mutant versus wild-type Men1 transcripts in thirteen tissues from mice carrying a heterozygous truncating mutation in the ubiquitously expressed Men1 gene.
Significant differences were found between two groups of tissues. The first group, which includes testis, ovary, brain and heart, displays a strong decrease of the nonsense transcript (average ratio of 18% of mutant versus wild-type Men1 transcripts, identical to the value measured in murine embryonic fibroblasts). The second group, comprising lung, intestine and thymus, shows much less pronounced NMD (average ratio of 35%). Importantly, the extent of degradation by NMD does not correlate with the expression level of eleven genes encoding proteins involved in NMD or with the expression level of the Men1 gene.
Mouse models are an attractive option to evaluate the efficiency of NMD in multiple mammalian tissues and organs, given that it is much easier to obtain these from a mouse than from a single individual carrying a germline truncating mutation. In this study, we have uncovered in the thirteen different murine tissues that we examined up to a two-fold difference in NMD efficiency.
无义介导的mRNA衰变（NMD）途径可检测并降解含有提前终止密码子的mRNA，从而防止潜在有害的截短蛋白的积累。有人提出这种机制的效率存在组织间差异，这可能对理解各种遗传疾病中的基因型-表型相关性具有重要意义。然而，缺乏支持这一假设的有力证据。在这里，我们通过测量在普遍表达的Men1基因中携带杂合截短突变的小鼠的13种组织中突变型与野生型Men1转录本的比例来探讨这个问题。
在两组组织之间发现了显著差异。第一组包括睾丸、卵巢、脑和心脏，其无义转录本显著减少（突变型与野生型Men1转录本的平均比例为18%，与在小鼠胚胎成纤维细胞中测得的值相同）。第二组包括肺、肠和胸腺，其NMD作用不太明显（平均比例为35%）。重要的是，NMD的降解程度与11个编码参与NMD的蛋白质的基因的表达水平或Men1基因的表达水平均无相关性。
鉴于从小鼠获取组织比从携带种系截短突变的个体获取组织要容易得多，小鼠模型是评估多种哺乳动物组织和器官中NMD效率的一个有吸引力的选择。在本研究中，我们在所检测的13种不同小鼠组织中发现NMD效率存在高达两倍的差异。
