Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.
Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia.
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DOI：
10.1002/humu.23950
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发表时间：
2020-03
期刊：
影响因子：
3.9
通讯作者：
Meng L
中科院分区：
文献类型：
--
作者：
Gu S;Chen CA;Rosenfeld JA;Cope H;Launay N;Flanigan KM;Waldrop MA;Schrader R;Juusola J;Goker-Alpan O;Milunsky A;Schlüter A;Troncoso M;Pujol A;Tan QK;Schaaf CP;Meng L
遗传性痉挛性截瘫（HSP）是一组以下肢无力和痉挛为主要症状的疾病。尽管HSP的许多遗传原因的描绘，一个显着的一部分与HSP的个人仍然分子未确诊。通过外显子组测序，我们确定了五个不相关的家庭与儿童期发病的非综合征性HSP，所有表现为进行性痉挛步态，腿阵挛，脚趾步行开始从7至8岁。在4个家系中发现了UBAP 1基因的重复性两个碱基对缺失（c.426_427delGA，p.K143Sfs*15），在第5个家系中检测到了类似的变异（c.475_476delTT，p.F159*）。该变异被证实是从头在两个家庭和遗传从一个受影响的父母在其他两个家庭。从一个病人的淋巴细胞中进行的RNA研究与从头c.426_427delGA变异表现出逃逸的无义介导的衰变的UBAP 1突变体转录，这表明产生的截短蛋白。在这项研究中鉴定的两种变体预计会导致截短的蛋白失去与泛素化蛋白结合的能力，因此似乎对转运蛋白-I复合物所需的内体特异性内体分选复合物的正常功能表现出显性负效应。
Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7 to 8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be denovo in two families and inherited from an affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific endosomal sorting complexes required for the transport-I complex.
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DOI：
10.1093/bioinformatics/btq235
发表时间：
2010-06-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
de Souza RF;Aravind L
通讯作者：
Aravind L
影响因子：
9.8
作者：
Fard, Mohammad Ali Farazi;Rebelo, Adriana P.;Faghihi, Mohammad Ali
通讯作者：
Faghihi, Mohammad Ali
影响因子：
4
作者：
Zivony-Elboum, Yifat;Westbroek, Wendy;Falik-Zaccai, Tzipora C.
通讯作者：
Falik-Zaccai, Tzipora C.
影响因子：
5.7
作者：
Agromayor, Monica;Soler, Nicolas;Caballe, Anna;Kueck, Tonya;Freund, Stefan M.;Allen, Mark D.;Bycroft, Mark;Perisic, Olga;Ye, Yu;McDonald, Bethan;Scheel, Hartmut;Hofmann, Kay;Neil, Stuart J. D.;Martin-Serrano, Juan;Williams, Roger L.
通讯作者：
Williams, Roger L.
影响因子：
9.2
作者：
Stefani, Flavia;Zhang, Ling;Woodman, Philip
通讯作者：
Woodman, Philip