RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS
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.
Article Details
Authors (82)
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
Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau and Centre de Référence Maladies Rares Déficiences Intellectuelles de Causes Rares, Assistance Publique-Hopitaux de Paris Sorbonne Université
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
Institute of Systems Biomedicine, School of Basic Medical Sciences