Dharmadhikari Avinash V, Abad Maria Alba, Khan Sheraz, Maroofian Reza, Sands Tristan T, Ullah Farid, Samejima Itaru, Shen Yanwen, Wear Martin A, Moore Kiara E, Kondakova Elena, Mitina Natalia, Schaub Theres, Lee Grace K, Umandap Christine H, Berger Sara M, Iglesias Alejandro D, Popp Bernt, Abou Jamra Rami, Gabriel Heinz, Rentas Stefan, Rippert Alyssa L, Gray Christopher, Izumi Kosuke, Conlin Laura K, Koboldt Daniel C, Mosher Theresa Mihalic, Hickey Scott E, Albert Dara V F, Norwood Haley, Lewanda Amy Feldman, Dai Hongzheng, Liu Pengfei, Mitani Tadahiro, Marafi Dana, Eker Hatice Koçak, Pehlivan Davut, Posey Jennifer E, Lippa Natalie C, Vena Natalie, Heinzen Erin L, Goldstein David B, Mignot Cyril, de Sainte Agathe Jean-Madeleine, Al-Sannaa Nouriya Abbas, Zamani Mina, Sadeghian Saeid, Azizimalamiri Reza, Seifia Tahere, Zaki Maha S, Abdel-Salam Ghada M H, Abdel-Hamid Mohamed S, Alabdi Lama, Alkuraya Fowzan Sami, Dawoud Heba, Lofty Aya, Bauer Peter, Zifarelli Giovanni, Afzal Erum, Zafar Faisal, Efthymiou Stephanie, Gossett Daniel, Towne Meghan C, Yeneabat Raey, Perez-Duenas Belen, Cazurro-Gutierrez Ana, Verdura Edgard, Cantarin-Extremera Veronica, Marques Ana do Vale, Helwak Aleksandra, Tollervey David, Wontakal Sandeep N, Aggarwal Vimla S, Rosenfeld Jill A, Tarabykin Victor, Ohta Shinya, Lupski James R, Houlden Henry, Earnshaw William C, Davis Erica E, Jeyaprakash A Arockia, Liao Jun
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA, 90027, USA.
Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Nat Commun. 2025 Feb 17;16(1):1703. doi: 10.1038/s41467-025-56876-w.
SPOUT1/CENP-32 encodes 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 in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants show reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicate that SPOUT1/CENP-32 missense 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-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS (SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.
SPOUT1/CENP - 32编码一种假定的SPOUT RNA甲基转移酶，该酶先前被鉴定为一种有丝分裂染色体相关蛋白。SPOUT1/CENP - 32的缺失会导致中心体与纺锤极分离以及染色体排列错误。借助基因匹配平台，我们在此确定了21个家庭中的28名患有神经发育迟缓的个体，这些个体通过外显子组/基因组测序检测到SPOUT1/CENP - 32存在双等位基因变异。斑马鱼spout1/cenp - 32突变体显示幼虫头部尺寸减小，同时伴有细胞凋亡，这可能与细胞周期进程改变有关。斑马鱼体内互补试验表明，在人类中鉴定出的SPOUT1/CENP - 32错义变异具有致病性。SPOUT1/CENP - 32的晶体结构分析表明，大多数与疾病相关的错义变异位于催化结构域内。此外，SPOUT1/CENP - 32反复出现的错义变异在体外显示出甲基转移酶活性降低，并且在人类细胞中中心体与纺锤极的连接受损。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相关发育迟缓、小头畸形、癫痫、身材矮小），其基础是有丝分裂纺锤体组织缺陷以及随之而来的染色体分离错误。
