1. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.
- Author
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Dharmadhikari AV, Abad MA, Khan S, Maroofian R, Sands TT, Ullah F, Samejima I, Shen Y, Wear MA, Moore KE, Kondakova E, Mitina N, Schaub T, Lee GK, Umandap CH, Berger SM, Iglesias AD, Popp B, Abou Jamra R, Gabriel H, Rentas S, Rippert AL, Gray C, Izumi K, Conlin LK, Koboldt DC, Mosher TM, Hickey SE, Albert DVF, Norwood H, Lewanda AF, Dai H, Liu P, Mitani T, Marafi D, Eker HK, Pehlivan D, Posey JE, Lippa NC, Vena N, Heinzen EL, Goldstein DB, Mignot C, de Sainte Agathe JM, Al-Sannaa NA, Zamani M, Sadeghian S, Azizimalamiri R, Seifia T, Zaki MS, Abdel-Salam GMH, Abdel-Hamid MS, Alabdi L, Alkuraya FS, Dawoud H, Lofty A, Bauer P, Zifarelli G, Afzal E, Zafar F, Efthymiou S, Gossett D, Towne MC, Yeneabat R, Perez-Duenas B, Cazurro-Gutierrez A, Verdura E, Cantarin-Extremera V, Marques ADV, Helwak A, Tollervey D, Wontakal SN, Aggarwal VS, Rosenfeld JA, Tarabykin V, Ohta S, Lupski JR, Houlden H, Earnshaw WC, Davis EE, Jeyaprakash AA, and Liao J
- Subjects
- Humans, Animals, Female, Male, Mutation, Missense, Centrosome metabolism, Methyltransferases metabolism, Methyltransferases genetics, Child, Microcephaly genetics, Microcephaly metabolism, Chromosome Segregation, Child, Preschool, Zebrafish, Spindle Apparatus metabolism, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism, Neurodevelopmental Disorders pathology
- 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., Competing Interests: Competing interests: BCM and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs clinical microarray analysis (CMA), clinical ES (cES), and clinical biochemical studies. JRL serves on the Scientific Advisory Board of the BG. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at BG Laboratories. JRL has stock ownership in 23andMe, is a paid consultant for Genomics International, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. DP provides consulting service for Ionis Pharmaceuticals. The other authors declare no competing interests., (© 2025. The Author(s).)
- Published
- 2025
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