RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.
RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.
复制标题
RNA 甲基转移酶 SPOUT1/CENP-32 将有丝分裂纺锤体组织与神经发育障碍 SpADMiSS 联系起来。
DOI：
10.1101/2024.01.09.23300329
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Dharmadhikari AV
中科院分区：
文献类型：
--
作者：
Dharmadhikari AV
SPOUT1/CENP-32编码一种可能的唾液RNA甲基转移酶，以前被认为是一种有丝分裂染色体相关蛋白。SPOUT1/CENP-32缺失会导致中心体脱离纺锤体极，导致染色体错位。在基因匹配平台的帮助下，我们从21个SPOUT1/CENP-32双等位基因变异的家系中鉴定出28例神经发育迟缓个体，通过外显子/基因组测序检测到。斑马鱼突变体1/CENP-32突变体表现出幼虫头部大小减小，伴随的细胞凋亡可能与细胞周期进程改变有关。斑马鱼体内互补分析表明，在人类中发现的SPOUT1/CENP-32错义变异是致病的。SPOUT1/CENP-32的晶体结构分析表明，大多数与疾病相关的错义变体位于催化结构域。此外，SPOUT1/CENP-32反复出现的错义变体在体外显示出甲基转移酶活性降低，并损害了人类细胞中中心体与纺锤体极的连接。因此，SPOUT1/CENP-32致病变异导致一种常染色体隐性神经发育障碍：SPADMiSS(SPOUT1相关发育延迟小头癫痫矮身材)，由有丝分裂纺锤体组织缺陷和随之而来的染色体分离错误支撑。
SPOUT1/CENP-32encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, here we identify 28 individuals with neurodevelopmental delays from 21 families with bi-allelic variants inSPOUT1/CENP-32detected by exome/genome sequencing. Zebrafishspout1/cenp-32mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate thatSPOUT1/CENP-32missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 reveals that most disease-associated missense variants are located within the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants show reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus,SPOUT1/CENP-32pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.