Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.
Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.
复制标题
剪接体基因PPIL1和PRP17中的突变引起神经退行性pontocerebellar垂体性发育不全。
DOI：
10.1016/j.neuron.2020.10.035
复制
发表时间：
2021-01-20
期刊：
影响因子：
16.2
通讯作者：
Gleeson JG
中科院分区：
文献类型：
--
作者：
Chai G;Webb A;Li C;Antaki D;Lee S;Breuss MW;Lang N;Stanley V;Anzenberg P;Yang X;Marshall T;Gaffney P;Wierenga KJ;Chung BH;Tsang MH;Pais LS;Lovgren AK;VanNoy GE;Rehm HL;Mirzaa G;Leon E;Diaz J;Neumann A;Kalverda AP;Manfield IW;Parry DA;Logan CV;Johnson CA;Bonthron DT;Valleley EMA;Issa MY;Abdel-Ghafar SF;Abdel-Hamid MS;Jennings P;Zaki MS;Sheridan E;Gleeson JG
常染色体隐性遗传性小脑发育不全和共济失调是一组异质性脑疾病，由几种基本细胞过程的破坏引起。在这里，我们确定了10个家庭表现出神经退行性疾病，涉及脑桥小脑发育不全与小头畸形（PCHM）。患者在编码剪接体组分肽基脯氨酰异构酶样-1（PPIL 1）或前RNA加工-17（PRP 17）的基因中存在双等位基因突变。小鼠敲除任一基因在早期胚胎发生中是致命的，而PPIL 1患者突变敲入小鼠显示神经元特异性凋亡。任一蛋白质的缺失都会影响剪接的完整性，主要影响短而高GC含量的内含子和参与脑疾病的基因。PPIL 1和PRP 17形成活性异构酶-底物相互作用，然而，我们发现异构酶活性对于功能不是关键的。因此，我们建立了破坏剪接完整性和“主要剪接体病”作为PCHM和神经变性的新机制，并揭示了剪接体脯氨酸异构酶的非酶功能。Chai等人发现，剪接因子PPIL 1和PRP 17的缺失导致神经退行性脑疾病，即使它们是酶-底物对，它们的功能也是为剪接体提供支架。
Autosomal-recessive cerebellar hypoplasia and ataxia comprise a group of heterogeneous brain disorders, caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic, mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein impacted splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, however, we found isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and ‘major spliceosome-opathies’ as a new mechanism underlying PCHM and neurodegeneration, and uncover a non-enzymatic function of a spliceosomal proline isomerase. Chai et al. discover that loss of splicing factors PPIL1 and PRP17 lead to a neurodegenerative brain disease, and even though they are an enzyme-substrate pair, they function instead to scaffold the spliceosome.
登录
查看更多内容
影响因子：
64.5
作者：
Karaca E;Weitzer S;Pehlivan D;Shiraishi H;Gogakos T;Hanada T;Jhangiani SN;Wiszniewski W;Withers M;Campbell IM;Erdin S;Isikay S;Franco LM;Gonzaga-Jauregui C;Gambin T;Gelowani V;Hunter JV;Yesil G;Koparir E;Yilmaz S;Brown M;Briskin D;Hafner M;Morozov P;Farazi TA;Bernreuther C;Glatzel M;Trattnig S;Friske J;Kronnerwetter C;Bainbridge MN;Gezdirici A;Seven M;Muzny DM;Boerwinkle E;Ozen M;Baylor Hopkins Center for Mendelian Genomics;Clausen T;Tuschl T;Yuksel A;Hess A;Gibbs RA;Martinez J;Penninger JM;Lupski JR
通讯作者：
Lupski JR
影响因子：
21.3
作者：
Gruber, Ralph;Zhou, Zhongwei;Wang, Zhao-Qi
通讯作者：
Wang, Zhao-Qi
影响因子：
5.3
作者：
Agafonov, Dmitry E.;Deckert, Jochen;Luehrmann, Reinhard
通讯作者：
Luehrmann, Reinhard
影响因子：
64.8
作者：
Bertram, Karl;Agafonov, Dmitry E.;Luehrmann, Reinhard
通讯作者：
Luehrmann, Reinhard
DOI：
10.1073/pnas.1613181114
发表时间：
2017-03-21
影响因子：
11.1
作者：
Jangi, Mohini;Fleet, Christina;Staropoli, John F.
通讯作者：
Staropoli, John F.