Language

English

Publication Date

2-17-2025

Journal

Nature Communications

DOI

10.1038/s41467-025-56876-w

PMID

39962046

PMCID

PMC11833075

PubMedCentral® Posted Date

2-17-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Zebrafish, Animals, Spindle Apparatus, Neurodevelopmental Disorders, Male, Mutation, Missense, Female, Zebrafish Proteins, Methyltransferases, Centrosome, Microcephaly, Pedigree, Child, Chromosome Segregation, Neurodevelopmental disorders, Mechanisms of disease, Mitotic spindle, Neurodevelopmental disorders

Published Open-Access

yes

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