Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome.
Increased protein stability of CDKN1C causes a gain-of-function phenotype in patients with IMAGe syndrome.
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CDKN1C的蛋白质稳定性提高会导致图像综合征患者的功能型表型。
DOI：
10.1371/journal.pone.0075137
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Saitoh S
中科院分区：
文献类型：
--
作者：
Hamajima N;Johmura Y;Suzuki S;Nakanishi M;Saitoh S
最近在影像综合征患者中发现了CDKN1C基因增殖细胞核抗原结合域的突变。然而，图像相关突变导致的增殖细胞核抗原结合缺失和CDKN1C单泛素化抑制很难解释图像综合征的生长减退表型特征。我们在这里证明了CDKN1C基因的图像相关突变显著提高了蛋白质的稳定性。我们在CDKN1C基因中发现了一种新的杂合突变，c.815T>；G(p.Ile272Ser)，在三个表现出与影像综合征相关的临床症状的兄弟姐妹及其母亲(未受影响的携带者)中。在P.Ile272Ser和另外两个与图像相关的突变p.Asp274Asn和p.Phe276Val的情况下，增殖细胞核抗原与CDKN1C的结合被破坏。有趣的是，图像相关突变CDKN1C蛋白即使在环己亚胺存在下也相当稳定，而野生型蛋白几乎完全通过蛋白酶体途径降解，这表明添加蛋白酶体抑制剂MG132没有降解。这些结果表明，IMAGE综合征的生长减少表型源于CDKN1C功能获得，这是由于IMAGE相关突变导致蛋白质稳定性增加。
Mutations in the proliferating cell nuclear antigen (PCNA)-binding domain of the CDKN1C gene were recently identified in patients with IMAGe syndrome. However, loss of PCNA binding and suppression of CDKN1C monoubiquitination by IMAGe-associated mutations hardly explain the reduced-growth phenotype characteristic of IMAGe syndrome. We demonstrate here that IMAGe-associated mutations in the CDKN1C gene dramatically increased the protein stability. We identified a novel heterozygous mutation, c.815T>G (p.Ile272Ser), in the CDKN1C gene in three siblings manifesting clinical symptoms associated with IMAGe syndrome and their mother (unaffected carrier). PCNA binding to CDKN1C was disrupted in the case of p.Ile272Ser, and for two other IMAGe-associated mutations, p.Asp274Asn and p.Phe276Val. Intriguingly, the IMAGe-associated mutant CDKN1C proteins were fairly stable even in the presence of cycloheximide, whereas the wild-type protein was almost completely degraded via the proteasome pathway, as shown by the lack of degradation with addition of a proteasome inhibitor, MG132. These results thus suggested that the reduced-growth phenotype of IMAGe syndrome derives from CDKN1C gain-of-function due to IMAGe-associated mutations driving increased protein stability.
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影响因子：
2
作者：
Amano, Naoko;Naoaki, Hori;Hasegawa, Tomonobu
通讯作者：
Hasegawa, Tomonobu
影响因子：
3.8
作者：
Hutz, JE;Krause, AS;Keegan, CE
通讯作者：
Keegan, CE
影响因子：
10.5
作者：
Yan, Y;Frisén, J;Barbacid, M
通讯作者：
Barbacid, M
影响因子：
30.8
作者：
Arboleda VA;Lee H;Parnaik R;Fleming A;Banerjee A;Ferraz-de-Souza B;Délot EC;Rodriguez-Fernandez IA;Braslavsky D;Bergadá I;Dell'Angelica EC;Nelson SF;Martinez-Agosto JA;Achermann JC;Vilain E
通讯作者：
Vilain E
影响因子：
--
作者：
Lienhardt, A;Mas, JC;Tauber, M
通讯作者：
Tauber, M