Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.
Protein instability associated with AARS1 and MARS1 mutations causes trichothiodystrophy.
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DOI：
10.1093/hmg/ddab123
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发表时间：
2021-08-28
影响因子：
3.5
通讯作者：
Vermeulen W
中科院分区：
文献类型：
--
作者：
Botta E;Theil AF;Raams A;Caligiuri G;Giachetti S;Bione S;Accadia M;Lombardi A;Smith DEC;Mendes MI;Swagemakers SMA;van der Spek PJ;Salomons GS;Hoeijmakers JHJ;Yesodharan D;Nampoothiri S;Ogi T;Lehmann AR;Orioli D;Vermeulen W
毛发硫营养不良（TTD）是一种罕见的遗传性神经发育障碍，其特征为缺硫的脆性毛发和指甲以及鳞状皮肤，但具有其他显著可变的临床特征。光敏TTD（PS-TTD）形式除了表现出进行性神经病变和节段性加速老化的其他特征外，还表现出与受损的基因组维持和转录相关的特征。对于不同的非光敏形式的TTD（NPS-TTD），已经确定了参与基因表达各个步骤的新因素，这些因素似乎没有显示出过早衰老的特征。在这里，我们确定丙氨酰-tRNA合成酶1和甲硫氨酰-tRNA合成酶1变异体作为新的基因缺陷，导致NPS-TTD。这些变体导致相应基因产物丙氨酰-和甲硫氨酰-tRNA合成酶的不稳定性。这些发现扩展了我们以前的观察，即TTD突变影响相应蛋白质的稳定性，并强调这种现象是TTD的共同特征。在受影响个体的皮肤成纤维细胞中进行的功能研究表明，这些新的变体也会影响tRNA充电的速率，这是蛋白质翻译的第一步。TTD因子丰度降低扩展到翻译和转录，重新定义TTD为一种参与基因表达的蛋白质不稳定的综合征。
Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder defined by sulfur-deficient brittle hair and nails and scaly skin, but with otherwise remarkably variable clinical features. The photosensitive TTD (PS-TTD) forms exhibits in addition to progressive neuropathy and other features of segmental accelerated aging and is associated with impaired genome maintenance and transcription. New factors involved in various steps of gene expression have been identified for the different non-photosensitive forms of TTD (NPS-TTD), which do not appear to show features of premature aging. Here, we identify alanyl-tRNA synthetase 1 and methionyl-tRNA synthetase 1 variants as new gene defects that cause NPS-TTD. These variants result in the instability of the respective gene products alanyl- and methionyl-tRNA synthetase. These findings extend our previous observations that TTD mutations affect the stability of the corresponding proteins and emphasize this phenomenon as a common feature of TTD. Functional studies in skin fibroblasts from affected individuals demonstrate that these new variants also impact on the rate of tRNA charging, which is the first step in protein translation. The extension of reduced abundance of TTD factors to translation as well as transcription redefines TTD as a syndrome in which proteins involved in gene expression are unstable.
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DOI：
10.1083/jcb.201709072
发表时间：
2018-01-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Klaips CL;Jayaraj GG;Hartl FU
通讯作者：
Hartl FU
影响因子：
3.8
作者：
Kleijer, Wim J.;Laugel, Vincent;Lehmann, Alan R.
通讯作者：
Lehmann, Alan R.
影响因子：
8.8
作者：
Alupei, Marius Costel;Maity, Pallab;Iben, Sebastian
通讯作者：
Iben, Sebastian
影响因子：
16
作者：
de Boer, J;de Wit, J;Weeda, G
通讯作者：
Weeda, G
DOI：
10.1136/jnnp-2013-305049
发表时间：
2013-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Gonzalez M;McLaughlin H;Houlden H;Guo M;Yo-Tsen L;Hadjivassilious M;Speziani F;Yang XL;Antonellis A;Reilly MM;Züchner S;Inherited Neuropathy Consortium
通讯作者：
Inherited Neuropathy Consortium