A Novel Mutation inRPL10(Ribosomal Protein L10) Causes X-Linked Intellectual Disability, Cerebellar Hypoplasia, and Spondylo-Epiphyseal Dysplasia

Abstract

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.

Prenatal diagnosis of posterior fossa anomalies: Additional value of chromosomal microarray analysis in fetuses with cerebellar hypoplasia

“…There are several chromosome abnormalities that may be associated with CH (Figure ) . Our results further demonstrate that the deletion of 5p15.33, 6q terminal deletion syndrome, and Xq28 duplication syndrome may be related with CH.…”

Ribosomal biogenesis as an emerging target of neurodevelopmental pathologies

“…A hemizygous RPL10 mutation that mapped to the N‐terminal region (A64V) was identified in two related male patients with ID and cerebellar hypoplasia (Zanni et al . ). That mutation was shown to increase general protein synthesis in the mutant yeast rpl10 complementation assay.…”

“…; Zanni et al . ). Additional phenotypic manifestations included mild microcephaly, cerebellar hypoplasia, and delayed neurodevelopment.…”

“…Indeed, the A64V RPL10 is able to rescue complete loss‐of‐function (LOF) mutants of yeast RPL10 (Zanni et al . ).…”

A Ribosomopathy Reveals Decoding Defective Ribosomes Driving Human Dysmorphism

“…These individuals also present with microcephaly, anteverted ears, a broad nasal ridge and epicanthus, myopia, urogenital anomalies, and a delay of motor development. [4][5][6] While almost all DBA-linked RP gene mutations studied to date are loss of function, 7 the fact that inherited variants of uS2 and uL16 exist in the absence of any hematopoietic phenotype suggests more mechanisms underlying the pathogenicity of these mutations remain to be uncovered. Further support for this comes from the discovery that somatic mutations in genes coding for uL16 and uL18 (RPL5) are associated with the malignancy T cell acute lymphoblastic leukemia.…”