Nature communications · 2025

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

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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

Аннотация

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.

Предметные рубрики MeSH

Humans Zebrafish Animals Spindle Apparatus Neurodevelopmental Disorders Male Mutation, Missense Female Zebrafish Proteins Methyltransferases Centrosome Microcephaly Pedigree Child Chromosome Segregation

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

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Аннотация

Предметные рубрики MeSH