title: A novel ribosomopathy caused by dysfunction of RPL10 disrupts neurodevelopment and causes X-linked microcephaly in humans.
abstract: Neurodevelopmental defects in humans represent a clinically heterogeneous group of disorders. Here, we report the genetic and functional dissection of a multigenerational pedigree with an X-linked syndromic disorder hallmarked by microcephaly, growth retardation, and seizures. Using an X-linked intellectual disability (XLID) next-generation sequencing diagnostic panel, we identified a novel missense mutation in the gene encoding 60S ribosomal protein L10 (RPL10), a locus associated previously with autism spectrum disorders (ASD); the p.K78E change segregated with disease under an X-linked recessive paradigm while, consistent with causality, carrier females exhibited skewed X inactivation. To examine the functional consequences of the p.K78E change, we modeled RPL10 dysfunction in zebrafish. We show that endogenous rpl10 expression is augmented in anterior structures, and that suppression decreases head size in developing morphant embryos, concomitant with reduced bulk translation and increased apoptosis in the brain. Subsequently, using in vivo complementation, we demonstrate that p.K78E is a loss-of-function variant. Together, our findings suggest that a mutation within the conserved N-terminal end of RPL10, a protein in close proximity to the peptidyl transferase active site of the 60S ribosomal subunit, causes severe defects in brain formation and function.
authors.affiliation: Department of Pediatrics, Rutgers Biomedical and Health Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Susan S
authors.identifier: http://orcid.org/0000-0002-1618-7127
authors.initials: SS
authors.lastname: Brooks
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Alissa L
authors.initials: AL
authors.lastname: Wall
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Christelle
authors.initials: C
authors.lastname: Golzio
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: David W
authors.initials: DW
authors.lastname: Reid
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Amalia
authors.initials: A
authors.lastname: Kondyles
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Willer
authors.affiliation: Department of Pediatrics, Rutgers Biomedical and Health Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901.
authors.forename: Christina
authors.initials: C
authors.lastname: Botti
authors.affiliation: Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710 Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Christopher V
authors.initials: CV
authors.lastname: Nicchitta
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Center for Human Disease Modeling, Duke University Medical Center, Durham, North Carolina 27710 erica.davis@duke.edu.
authors.forename: Erica E
authors.identifier: http://orcid.org/0000-0002-2412-8397
authors.initials: EE
authors.lastname: Davis
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D049109:Cell Proliferation; D002675:Child, Preschool; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish
chemical_list: C000630686:RPL10 protein, human; D012269:Ribosomal Proteins
keywords: X-linked; microcephaly; ribosome; translational elongation; zebrafish