An empirical pipeline for personalized diagnosis of Lafora disease mutations.
An empirical pipeline for personalized diagnosis of Lafora disease mutations.
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DOI：
10.1016/j.isci.2021.103276
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发表时间：
2021-11-19
期刊：
影响因子：
5.8
通讯作者：
Gentry MS
中科院分区：
文献类型：
--
作者：
Brewer MK;Machio-Castello M;Viana R;Wayne JL;Kuchtová A;Simmons ZR;Sternbach S;Li S;García-Gimeno MA;Serratosa JM;Sanz P;Vander Kooi CW;Gentry MS
Lafora病(LD)是一种致命的儿童痴呆，其特征是青少年时期表现为进行性肌阵挛癫痫，神经功能迅速下降，通常在发病10年内死亡。编码糖原磷酸酶Laforin的EPM2A或编码E3连接酶Malin的EPM2B的突变会导致LD。整个外显子组测序已经发现了许多EPM2A变异与晚发或较慢的疾病进展有关。我们建立了一条经验管道，用于使用互补的生化方法在体外表征Laforin错义突变的功能后果。对26个突变的分析显示，不同的功能类别与不同的结果相关，这得到了临床病例的支持。例如，F321C和G279C突变会减弱功能缺陷，并与进展缓慢相关。这条管道能够对新发现的EPM2A突变进行快速表征和分类，为临床医生和研究人员提供基因信息来指导LD患者的治疗。拉福拉病(LD)患者表现出不同的临床进展LD错义突变不同地影响拉福林功能体外实验流水线被用于对拉福林错义突变进行分类根据突变类别疾病；生物化学；结构生物学；生物物理学
Lafora disease (LD) is a fatal childhood dementia characterized by progressive myoclonic epilepsy manifesting in the teenage years, rapid neurological decline, and death typically within ten years of onset. Mutations in either EPM2A, encoding the glycogen phosphatase laforin, or EPM2B, encoding the E3 ligase malin, cause LD. Whole exome sequencing has revealed many EPM2A variants associated with late-onset or slower disease progression. We established an empirical pipeline for characterizing the functional consequences of laforin missense mutations in vitro using complementary biochemical approaches. Analysis of 26 mutations revealed distinct functional classes associated with different outcomes that were supported by clinical cases. For example, F321C and G279C mutations have attenuated functional defects and are associated with slow progression. This pipeline enabled rapid characterization and classification of newly identified EPM2A mutations, providing clinicians and researchers genetic information to guide treatment of LD patients. Lafora disease (LD) patients present with varying clinical progression LD missense mutations differentially affect laforin function An empirical in vitro pipeline is used to classify laforin missense mutations Patient progression can be predicted based on mutation class Disease; Biochemistry; Structural biology; Biophysics
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影响因子：
2.2
作者：
Garcia-Gimeno MA;Rodilla-Ramirez PN;Viana R;Salas-Puig X;Brewer MK;Gentry MS;Sanz P
通讯作者：
Sanz P
影响因子：
3.9
作者：
Hicks, Stephanie;Wheeler, David A.;Plon, Sharon E.;Kimmel, Marek
通讯作者：
Kimmel, Marek
影响因子：
2.6
作者：
Gentry, Matthew S.;Afawi, Zaid;Serratosa, Jose M.
通讯作者：
Serratosa, Jose M.
影响因子：
3.5
作者：
Ganesh, S;Delgado-Escueta, A;Yamakawa, K
通讯作者：
Yamakawa, K
影响因子：
4.9
作者：
Austin, Grant L.;Simmons, Zoe R.;Gentry, Matthew S.
通讯作者：
Gentry, Matthew S.