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Am J Hum Genet. 2019 Nov 7;105(5):1040-1047. doi: 10.1016/j.ajhg.2019.09.024. Epub 2019 Oct 17.

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Author information

1
CHU Nantes, Service de génétique médicale, F-44000 Nantes, France.
2
Nantes Université, INSERM, Bone sarcomas and remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France.
3
Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), Université de Toulouse, UPS, CNRS, 31062 Toulouse, France.
4
L'institut du thorax, INSERM, CNRS, Université de Nantes, F-44000 Nantes, France.
5
Nantes Université, CNRS, Unité Fonctionnalité et Ingénierie des Protéines (UFIP), UMR CNRS 6286, F-44000 Nantes, France.
6
INSERM U1149/ERL 8252, Inflammation Research Center, 75018 Paris, France.
7
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
8
Children's of Alabama, Department of Orthopaedic Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
9
Genetic Institute, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.
10
Pediatric Orthopedic Department, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.
11
Service d'Orthopédie Pédiatrique, CHU de Nantes, F-44000 Nantes, France.
12
Service de Chirurgie Orthopédique Pédiatrique, CHU de Tours, 37044 Tours, France.
13
CRB/Tumorothèque, CHU de Tours, 37044 Tours, France.
14
Etablissement Français du Sang, F-44000 Nantes, France; CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, F-44000 Nantes, France.
15
Center for Genomics and Transcriptomics and Praxis für Humangenetik Tübingen, 72076 Tübingen, Germany.
16
GeneDx, Gaithersburg, MD 20877, USA.
17
INSERM U1149/ERL 8252, Inflammation Research Center, 75018 Paris, France; AP-HP, Service d'Hématologie Biologique, Hôpital R. Debré, Université Paris 7 Denis Diderot, Sorbonne Paris Cité, 75019 Paris, France.
18
Service de Génétique, CHU de Tours, 37044 Tours, France.
19
Nantes Université, CHU Nantes, INSERM, Bone sarcomas and remodeling of calcified tissues, UMR 1238, F-44000 Nantes, France. Electronic address: marc.baudhuin@univ-nantes.fr.
20
CHU Nantes, Service de génétique médicale, F-44000 Nantes, France. Electronic address: bertrand.isidor@chu-nantes.fr.

Abstract

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.

KEYWORDS:

RPL13; Spondyloepimetaphyseal dysplasia; bone dysplasia; chondrodysplasia; ribosome; short stature

PMID:
31630789
PMCID:
PMC6849359
[Available on 2020-05-07]
DOI:
10.1016/j.ajhg.2019.09.024

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