Nature Communications (Feb 2025)
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 de Sainte 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,
- Jun Liao
Affiliations
- Avinash V. Dharmadhikari
- Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles
- Maria Alba Abad
- Institute of Cell Biology, University of Edinburgh
- Sheraz Khan
- Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago
- Reza Maroofian
- Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology
- Tristan T. Sands
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University
- Farid Ullah
- Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago
- Itaru Samejima
- Institute of Cell Biology, University of Edinburgh
- Yanwen Shen
- Translational Research Center for the Nervous System, Brain Cognition and Brain Disease Institute (BCBDI), Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
- Martin A. Wear
- Edinburgh Protein Production Facility (EPPF), University of Edinburgh, King’s Buildings, Max Born Crescent
- Kiara E. Moore
- Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago
- Elena Kondakova
- Institute of Neuroscience, Laboratory of Genetics of Brain Development, National Research Lobachevsky State University of Nizhny Novgorod
- Natalia Mitina
- Institute of Neuroscience, Laboratory of Genetics of Brain Development, National Research Lobachevsky State University of Nizhny Novgorod
- Theres Schaub
- Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin
- Grace K. Lee
- Personalized Care (PCARE) Program, Department of Pathology and Laboratory Medicine; The Saban Research Institute, Children’s Hospital Los Angeles
- Christine H. Umandap
- Medical Genetics, DMG Children’s Rehabilitative Services
- Sara M. Berger
- Division of Clinical Genetics, Department of Pediatrics, Columbia University, Vagelos College of Physicians and Surgeons
- Alejandro D. Iglesias
- Division of Clinical Genetics, Department of Pediatrics, Columbia University, Vagelos College of Physicians and Surgeons
- Bernt Popp
- Institute of Human Genetics, University of Leipzig Medical Center
- Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center
- Heinz Gabriel
- Praxisfür Humangenetik Tübingen
- Stefan Rentas
- Department of Pathology, Duke University School of Medicine
- Alyssa L. Rippert
- Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia
- Christopher Gray
- Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia
- Kosuke Izumi
- Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia
- Laura K. Conlin
- Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia
- Daniel C. Koboldt
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital
- Theresa Mihalic Mosher
- Ambry Genetics
- Scott E. Hickey
- Department of Pediatrics, The Ohio State University College of Medicine
- Dara V. F. Albert
- Department of Pediatrics, The Ohio State University College of Medicine
- Haley Norwood
- GeneDx, LLC.
- Amy Feldman Lewanda
- Rare Disease Institute, Children’s National Hospital
- Hongzheng Dai
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Tadahiro Mitani
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Dana Marafi
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Hatice Koçak Eker
- Department of Medical Genetics, Konya City Hospital
- Davut Pehlivan
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Jennifer E. Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Natalie C. Lippa
- Department of Medicine, Columbia University Irving Medical Center
- Natalie Vena
- Department of Medicine, Columbia University Irving Medical Center
- Erin L. Heinzen
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina
- David B. Goldstein
- Institute for Genomic Medicine, Columbia University Irving Medical Center
- Cyril Mignot
- Département de Génétique, APHP Sorbonne Université
- Jean-Madeleine de Sainte Agathe
- Department of Medical Genetics, Groupe Hospitalo-Universitaire Pitié-Salpêtrière, AP-HP.Sorbonne Université
- Nouriya Abbas Al-Sannaa
- Pediatric Services, John Hopkins Aramco Health Care
- Mina Zamani
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz
- Saeid Sadeghian
- Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences
- Reza Azizimalamiri
- Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences
- Tahere Seifia
- Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz
- Maha S. Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre
- Ghada M. H. Abdel-Salam
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre
- Mohamed S. Abdel-Hamid
- Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre
- Lama Alabdi
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Fowzan Sami Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
- Heba Dawoud
- Pediatrics Department, Faculty of Medicine, Tanta University
- Aya Lofty
- Pediatrics Department, Faculty of Medicine, Tanta University
- Peter Bauer
- CENTOGENE GmbH
- Giovanni Zifarelli
- CENTOGENE GmbH
- Erum Afzal
- Department of Development Pediatrics, The Children’s Hospital and The Institute of Child Health
- Faisal Zafar
- Department of Development Pediatrics, The Children’s Hospital and The Institute of Child Health
- Stephanie Efthymiou
- Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology
- Daniel Gossett
- Texas Child Neurology
- Meghan C. Towne
- Ambry Genetics
- Raey Yeneabat
- Departments of Pathology and Genetic Medicine, Johns Hopkins University School of Medicine
- Belen Perez-Duenas
- Department of Paediatric Neurology, Hospital Vall d’Hebron
- Ana Cazurro-Gutierrez
- Vall d’Hebron Research Institute
- Edgard Verdura
- Vall d’Hebron Research Institute
- Veronica Cantarin-Extremera
- Department of Paediatric Neurology, Hospital Infantil Niño Jesús
- Ana do Vale Marques
- Gene Center, Department of Biochemistry, Ludwig-Maximilians Universität
- Aleksandra Helwak
- Institute of Cell Biology, University of Edinburgh
- David Tollervey
- Institute of Cell Biology, University of Edinburgh
- Sandeep N. Wontakal
- Departments of Pathology and Genetic Medicine, Johns Hopkins University School of Medicine
- Vimla S. Aggarwal
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- Jill A. Rosenfeld
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Victor Tarabykin
- Institute of Neuroscience, Laboratory of Genetics of Brain Development, National Research Lobachevsky State University of Nizhny Novgorod
- Shinya Ohta
- Institute for Genetic Medicine Pathophysiology, Hokkaido University
- James R. Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Henry Houlden
- Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology
- William C. Earnshaw
- Institute of Cell Biology, University of Edinburgh
- Erica E. Davis
- Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago
- A. Arockia Jeyaprakash
- Institute of Cell Biology, University of Edinburgh
- Jun Liao
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center
- DOI
- https://doi.org/10.1038/s41467-025-56876-w
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 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.
