Dataset Information

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

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.

SUBMITTER: Le Caignec C

PROVIDER: S-EPMC6849359 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Le Caignec Cedric C Ory Benjamin B Lamoureux François F O'Donohue Marie-Francoise MF Orgebin Emilien E Lindenbaum Pierre P Téletchéa Stéphane S Saby Manon M Hurst Anna A Nelson Katherine K Gilbert Shawn R SR Wilnai Yael Y Zeitlin Leonid L Segev Eitan E Tesfaye Robel R Nizon Mathilde M Cogne Benjamin B Bezieau Stéphane S Geoffroy Loic L Hamel Antoine A Mayrargue Emmanuelle E de Courtivron Benoît B Decock-Giraudaud Aliette A Charrier Céline C Pichon Olivier O Retière Christelle C Redon Richard R Pepler Alexander A McWalter Kirsty K Da Costa Lydie L Toutain Annick A Gleizes Pierre-Emmanuel PE Baud'huin Marc M Isidor Bertrand B

American journal of human genetics 20191017 5

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 in ...[more]

PMID: 31630789

Similar Datasets

Project description:BackgroundLinear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.Case presentationWe report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.ConclusionWe investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.

Dataset Information

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Publications

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets