RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS
Dharmadhikari, Avinash V. (University of Southern California)
Abad, Maria Alba (University of Edinburgh)
Maroofian, R. (University College London)
Kondakova, Elena (National Research Lobachevsky State University of Nizhny Novgorod)
Iglesias, Alejandro D. (Vagelos College of Physicians and Surgeons)
Popp, Bernt (University of Leipzig Medical Center)
Abou Jamra, Rami (University of Leipzig Medical Center)
Koboldt, Daniel C. (The Ohio State University College of Medicine)
Lewanda, Amy Feldman (Children's National Hospital)
Liu, Pengfei (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Marafi, Dana (Kuwait University)
Posey, Jennifer E. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Heinzen, Erin L. (University of North Carolina)
Goldstein, David B. (Columbia University Irving Medical Center)
Mignot, Cyril (APHP Sorbonne Université)
de Sainte Agathe, Jean-Madeleine (AP-HP Sorbonne Université)
Sadeghian, Saeid (Ahvaz Jundishapur University of Medical Sciences)
Zaki, Maha (National Research Centre (Cairo, Egipte))
Abdel-Salam, Ghada M. H. (National Research Centre (Cairo, Egipte))
Alabdi, Lama (King Faisal Specialist Hospital and Research Centre (Aràbia Saudita))
Alkuraya, Fowzan S. (King Faisal Specialist Hospital and Research Centre (Aràbia Saudita))
Efthymiou, Stephanie (University College London (Regne Unit))
Verdura, Edgard (Vall d'Hebron Institut de Recerca (VHIR))
Helwak, Aleksandra (University of Edinburgh)
Tollervey, David (University of Edinburgh)
Wontakal, Sandeep N. (Johns Hopkins University School of Medicine)
Rosenfeld, Jill A. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Tarabykin, Victor (Charité Universitätsmedizin Berlin)
Lupski, James R. (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Houlden, Henry (University College London)
Earnshaw, William C. (University of Edinburgh)
Davis, Erica E. (Northwestern University Feinberg School of Medicine)
Jeyaprakash, A. Arockia (Hospital Clínic i Provincial de Barcelona)
Liao, Jun (Columbia University Irving Medical Center)
Khan, Sheraz (Pakistan Institute of Engineering and Applied Sciences)
Sands, Tristan T. (Columbia University)
Ullah, Farid (Northwestern University Feinberg School of Medicine)
Samejima, Itaru (University of Edinburgh)
Shen, Yanwen (Fujian Medical University Union Hospital)
Wear, Martin A. (University of Edinburgh)
Moore, Kiara E. (Northwestern University Feinberg School of Medicine)
Mitina, Natalia (National Research Lobachevsky State University of Nizhny Novgorod)
Schaub, Theres (Charité-Universitätsmedizin Berlin)
Lee, Grace K. (Children's Hospital Los Angeles (Estats Units d'Amèrica))
Umandap, Christine H. (Columbia University Vagelos College of Physicians and Surgeons (Estats Units d'Amèrica))
Berger, Sara M. (Columbia University Vagelos College of Physicians and Surgeons (Estats Units d'Amèrica))
Gabriel, Heinz (Praxis für Humangenetik Tübingen)
Rentas, Stefan (Duke University School of Medicine)
Rippert, Alyssa L. (Children's Hospital of Philadelphia (Pennsilvània))
Gray, Christopher B. (Children's Hospital of Philadelphia (Pennsilvània))
Izumi, Kosuke (Children's Hospital of Philadelphia (Pennsilvània))
Conlin, Laura K. (Children's Hospital of Philadelphia (Pennsilvània))
Mosher, Theresa Mihalic (Ambry Genetics (Aliso Viejo, Estats Units d'Amèrica))
Hickey, Scott E. (Nationwide Children's Hospital)
Albert, Dara V. F. (Nationwide Children's Hospital)
Norwood, Haley (GeneDx)
Dai, Hongzheng (Baylor Genetics)
Mitani, Tadahiro (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Eker, Hatice Koçak (Konya City Hospital)
Pehlivan, Davut (Baylor College of Medicine (Houston, Estats Units d'Amèrica))
Lippa, Natalie C. (Columbia University Irving Medical Center)
Vena, Natalie (Columbia University Irving Medical Center)
Al-Sannaa, Nouriya Abbas (Johns Hopkins University School of Medicine)
Zamani, Mina (Narges Laboratory (Ahvaz, Iran))
Azizimalamiri, Reza (Ahvaz Jundishapur University of Medical Sciences)
Seifia, Tahere (Narges Laboratory (Ahvaz, Iran))
Abdel-Hamid, Mohamed S. (National Research Centre. Clinical Genetics Department, Human Genetics and Genome Research Institute (El Caire, Egipte))
Dawoud, Heba (Tanta University)
Lofty, Aya (Tanta University)
Bauer, Peter (CENTOGENE GmbH (Rostock, Alemanya))
Zifarelli, Giovanni (CENTOGENE GmbH (Rostock, Alemanya))
Afzal, Erum (The Children's Hospital and The Institute of Child Health (Multan, Pakistan))
Gossett, Daniel (Neurology Consultants of Dallas)
Towne, Meghan C. (Ambry Genetics (Aliso Viejo, Estats Units d'Amèrica))
Yeneabat, Raey (Johns Hopkins University School of Medicine)
Pérez-Dueñas, Belén (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Cazurro Gutiérrez, Ana Laura (Universitat Autònoma de Barcelona. Departament de Pediatria, Obstetrícia i Ginecologia i de Medicina Preventiva i Salut Pública)
Cantarin-Extremera, Veronica (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Marques, Ana do Vale (Ludwig-Maximilians Universität)
Aggarwal, Vimla S. (Columbia University Irving Medical Center. Department of Pathology and Cell Biology)
Ohta, Shinya (Hokkaido University)
Universitat Autònoma de Barcelona. Departament de Medicina

Data:	2025
Resum:	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. The RNA methyltransferase activity of SPOUT1/CENP-32 is crucial for accurate mitotic spindle organization. Here, the authors describe a neurodevelopmental disorder caused by bi-allelic pathogenic SPOUT1 variants with reduced activity and compromised function in spindle organization.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Neurodevelopmental disorders ; Mechanisms of disease ; Mitotic spindle
Publicat a:	Nature communications, Vol. 16 (February 2025) , art. 1703, ISSN 2041-1723

DOI: 10.1038/s41467-025-56876-w
PMID: 39962046

24 p, 4.8 MB

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