A Novel Mutation in RPL10 (Ribosomal Protein L10) Causes X-Linked Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia.
RPL10 encodes ribosomal protein L10 (uL16), a highly conserved multifunctional component of the large ribosomal subunit, involved in ribosome biogenesis and function. Using X-exome resequencing, we identified a novel missense mutation (c.191C>T; p.(A64V)) in the N-terminal domain of the protein, in a family with two affected cousins presenting with X-linked intellectual disability, cerebellar hypoplasia, and spondylo-epiphyseal dysplasia (SED). We assessed the impact of the mutation on the translational capacity of the cell using yeast as model system. The mutation generates a functional ribosomal protein, able to complement the translational defects of a conditional lethal mutation of yeast rpl10. However, unlike previously reported mutations, this novel RPL10 missense mutation results in an increase in the actively translating ribosome population. Our results expand the mutational and clinical spectrum of RPL10 identifying a new genetic cause of SED and highlight the emerging role of ribosomal proteins in the pathogenesis of neurodevelopmental disorders.
Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Ginevra
G
Zanni
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Vera M
VM
Kalscheuer
Department of Cell Biology, University of Salzburg, Salzburg, Austria.
Andreas
A
Friedrich
Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Sabina
S
Barresi
Unit of Child Neuropsychiatry, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Paolo
P
Alfieri
Unit of Neurology, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Matteo
M
Di Capua
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
Stefan A
SA
Haas
Unit of Child Neuropsychiatry, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Giorgia
G
Piccini
Department of Cell Biology, University of Salzburg, Salzburg, Austria.
Thomas
T
Karl
Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Sabine M
SM
Klauck
Research Laboratories, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Emanuele
E
Bellacchio
Unit of Nephrology, Department of Pediatrics, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Francesco
F
Emma
Unit of Clinical Endocrinology, Department of Pediatrics, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Marco
M
Cappa
Unit of Molecular Medicine for Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, IRRCS, Rome, Italy.
Enrico
E
Bertini
Department of Cell Biology, University of Salzburg, Salzburg, Austria.
Lore
L
Breitenbach-Koller
D002531:Cerebellum / Q000002:abnormalities*; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009421:Nervous System Malformations / Q000175:diagnosis / Q000235:genetics*; D059906:Neuroimaging; D010009:Osteochondrodysplasias / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D000080882:Ribosomal Protein L10; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D049951:X Chromosome Inactivation
C000630686:RPL10 protein, human; D012269:Ribosomal Proteins
RPL10; XLID; cerebellar hypoplasia; spondylo-epiphyseal dysplasia; uL16