Møller Lisbeth Birk, Schönewolf-Greulich Bitten, Rosengren Thomas, Larsen Lasse Jonsgaard, Ostergaard John R, Sommerlund Mette, Ostenfeldt Caroline, Stausbøl-Grøn Brian, Linnet Karen Markussen, Gregersen Pernille Axél, Jensen Uffe Birk
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark; Department of Science and Environment, Roskilde University, Roskilde, Denmark.
Applied Human Molecular Genetics, Clinical Genetics Clinic, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.
Mol Genet Metab. 2017 Apr;120(4):384-391. doi: 10.1016/j.ymgme.2017.02.008. Epub 2017 Mar 1.
TSC1 and TSC2 are genes mutated in the syndrome TSC (tuberous sclerosis complex). We describe a 3-generation family with 17 affected members, all presenting classic TSC features except renal manifestations. The disease segregates with a silent substitution in TSC2, c.4149C>T, p.(Ser1383Ser), which leads to the formation of an active donor splice site, resulting in three shorter alternatively spliced transcripts with premature stop codons. However a small amount of normal spliced transcript is apparently produced from the mutated allele, which might explain the milder phenotype. The gene products of TSC1/2 form a complex which at energy limiting states, down-regulates the activity of the regulator of protein synthesis, the mammalian target of rapamycin complex1 (mTORC1). As expected, in contrast to cultured control fibroblasts, starvation of cultured patient fibroblasts obtained from a hypomelanotic macule did not lead to repression of mTORC1, whereas partial repression was observed in patient fibroblasts obtained from non-lesional skin. The findings indicate that the development of hypomelanotic macules is associated with constitutive activated mTORC1, whereas mild deregulation of mTORC1 allows the maintenance of normal skin. Furthermore, the finding establishes the pathogenic effect of the "silent" c.4149C>T substitution and emphasizes the need for awareness when interpreting silent substitutions in general.
TSC1和TSC2是在结节性硬化症（TSC，结节性硬化复合体）中发生突变的基因。我们描述了一个三代家族，有17名受累成员，除肾脏表现外，均呈现典型的TSC特征。该疾病与TSC2中的一个沉默替代突变c.4149C>T，p.(Ser1383Ser)共分离，这导致形成一个活跃的供体剪接位点，产生三种带有过早终止密码子的较短的可变剪接转录本。然而，突变等位基因显然产生了少量正常剪接的转录本，这可能解释了较轻的表型。TSC1/2的基因产物形成一个复合体，在能量限制状态下，下调蛋白质合成调节因子哺乳动物雷帕霉素靶蛋白复合体1（mTORC1）的活性。正如预期的那样，与培养的对照成纤维细胞相比，从色素减退斑获取的培养患者成纤维细胞饥饿处理后并未导致mTORC1的抑制，而从非皮损处皮肤获取的患者成纤维细胞则观察到部分抑制。这些发现表明，色素减退斑的发生与组成性激活的mTORC1相关，而mTORC1的轻度失调允许正常皮肤的维持。此外，这一发现确立了“沉默”的c.4149C>T替代的致病作用，并强调了在一般情况下解释沉默替代时提高认识的必要性。
