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

Avinash V. Dharmadhikari, Maria Alba Abad, Sheraz Khan, Reza Maroofian, Tristan T. Sands, Farid Ullah, Itaru Samejima, Yanwen Shen, Martin A. Wear, Kiara E. Moore, Elena Kondakova, Natalia Mitina, Theres Schaub, Grace K. Lee, Christine H. Umandap, Sara M. Berger, Alejandro D. Iglesias, Bernt Popp, Rami Abou Jamra, Heinz Gabriel, Stefan Rentas, Alyssa L. Rippert, Christopher Gray, Kosuke Izumi, Laura K. Conlin, Daniel C. Koboldt, Theresa Mihalic Mosher, Scott E. Hickey, Dara V. F. Albert, Haley Norwood, Amy Feldman Lewanda, Hongzheng Dai, Pengfei Liu, Tadahiro Mitani, Dana Marafi, Hatice Koçak Eker, Davut Pehlivan, Jennifer E. Posey, Natalie C. Lippa, Natalie Vena, Erin L. Heinzen, David B. Goldstein, Cyril Mignot, Jean-Madeleine Agathe, Nouriya Abbas Al-Sannaa, Mina Zamani, Saeid Sadeghian, Reza Azizimalamiri, Tahere Seifia, Maha S. Zaki, Ghada M. H. Abdel-Salam, Mohamed S. Abdel-Hamid, Lama Alabdi, Fowzan Sami Alkuraya, Heba Dawoud, Aya Lofty, Peter Bauer, Giovanni Zifarelli, Erum Afzal, Faisal Zafar, Stephanie Efthymiou, Daniel Gossett, Meghan C. Towne, Raey Yeneabat, Belen Perez-Duenas, Ana Cazurro-Gutierrez, Edgard Verdura, Veronica Cantarin-Extremera, Ana do Vale Marques, Aleksandra Helwak, David Tollervey, Sandeep N. Wontakal, Vimla S. Aggarwal, Jill A. Rosenfeld, Victor Tarabykin, Shinya Ohta, James R. Lupski, Henry Houlden, William C. Earnshaw, Erica E. Davis (), A. Arockia Jeyaprakash () and Jun Liao ()
Additional contact information
Avinash V. Dharmadhikari: Children’s Hospital Los Angeles
Maria Alba Abad: University of Edinburgh
Sheraz Khan: Ann & Robert H. Lurie Children’s Hospital of Chicago
Reza Maroofian: Institute of Neurology
Tristan T. Sands: Columbia University
Farid Ullah: Ann & Robert H. Lurie Children’s Hospital of Chicago
Itaru Samejima: University of Edinburgh
Yanwen Shen: Chinese Academy of Sciences
Martin A. Wear: Max Born Crescent
Kiara E. Moore: Ann & Robert H. Lurie Children’s Hospital of Chicago
Elena Kondakova: National Research Lobachevsky State University of Nizhny Novgorod
Natalia Mitina: National Research Lobachevsky State University of Nizhny Novgorod
Theres Schaub: Charité Universitätsmedizin Berlin
Grace K. Lee: Children’s Hospital Los Angeles
Christine H. Umandap: DMG Children’s Rehabilitative Services
Sara M. Berger: Vagelos College of Physicians and Surgeons
Alejandro D. Iglesias: Vagelos College of Physicians and Surgeons
Bernt Popp: University of Leipzig Medical Center
Rami Abou Jamra: University of Leipzig Medical Center
Heinz Gabriel: Praxisfür Humangenetik Tübingen
Stefan Rentas: Duke University School of Medicine
Alyssa L. Rippert: Children’s Hospital of Philadelphia
Christopher Gray: Children’s Hospital of Philadelphia
Kosuke Izumi: Children’s Hospital of Philadelphia
Laura K. Conlin: Children’s Hospital of Philadelphia
Daniel C. Koboldt: Nationwide Children’s Hospital
Theresa Mihalic Mosher: Ambry Genetics
Scott E. Hickey: The Ohio State University College of Medicine
Dara V. F. Albert: The Ohio State University College of Medicine
Haley Norwood: LLC.
Amy Feldman Lewanda: Children’s National Hospital
Hongzheng Dai: Baylor College of Medicine
Tadahiro Mitani: Baylor College of Medicine
Dana Marafi: Baylor College of Medicine
Hatice Koçak Eker: Konya City Hospital
Davut Pehlivan: Baylor College of Medicine
Jennifer E. Posey: Baylor College of Medicine
Natalie C. Lippa: Columbia University Irving Medical Center
Natalie Vena: Columbia University Irving Medical Center
Erin L. Heinzen: University of North Carolina
David B. Goldstein: Columbia University Irving Medical Center
Cyril Mignot: APHP Sorbonne Université
Jean-Madeleine Agathe: AP-HP.Sorbonne Université
Nouriya Abbas Al-Sannaa: John Hopkins Aramco Health Care
Mina Zamani: Shahid Chamran University of Ahvaz
Saeid Sadeghian: Ahvaz Jundishapur University of Medical Sciences
Reza Azizimalamiri: Ahvaz Jundishapur University of Medical Sciences
Tahere Seifia: Shahid Chamran University of Ahvaz
Maha S. Zaki: National Research Centre
Ghada M. H. Abdel-Salam: National Research Centre
Mohamed S. Abdel-Hamid: National Research Centre
Lama Alabdi: King Faisal Specialist Hospital and Research Center
Fowzan Sami Alkuraya: King Faisal Specialist Hospital and Research Center
Heba Dawoud: Tanta University
Aya Lofty: Tanta University
Peter Bauer: CENTOGENE GmbH
Giovanni Zifarelli: CENTOGENE GmbH
Erum Afzal: The Children’s Hospital and The Institute of Child Health
Faisal Zafar: The Children’s Hospital and The Institute of Child Health
Stephanie Efthymiou: Institute of Neurology
Daniel Gossett: Texas Child Neurology
Meghan C. Towne: Ambry Genetics
Raey Yeneabat: Johns Hopkins University School of Medicine
Belen Perez-Duenas: Hospital Vall d’Hebron
Ana Cazurro-Gutierrez: Vall d’Hebron Research Institute
Edgard Verdura: Vall d’Hebron Research Institute
Veronica Cantarin-Extremera: Hospital Infantil Niño Jesús
Ana do Vale Marques: Ludwig-Maximilians Universität
Aleksandra Helwak: University of Edinburgh
David Tollervey: University of Edinburgh
Sandeep N. Wontakal: Johns Hopkins University School of Medicine
Vimla S. Aggarwal: Columbia University Irving Medical Center
Jill A. Rosenfeld: Baylor College of Medicine
Victor Tarabykin: National Research Lobachevsky State University of Nizhny Novgorod
Shinya Ohta: Hokkaido University
James R. Lupski: Baylor College of Medicine
Henry Houlden: Institute of Neurology
William C. Earnshaw: University of Edinburgh
Erica E. Davis: Ann & Robert H. Lurie Children’s Hospital of Chicago
A. Arockia Jeyaprakash: University of Edinburgh
Jun Liao: Columbia University Irving Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-56876-w

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