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.477þ1G>T, c.477þ1G>A, and c.477þ2 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.

Sequence variation, common tissue expression patterns and learning models: a genome-wide survey of vertebrate ribosomal proteins

“…For those five core RPs with the lowest similarity levels across vertebrates—namely: RPL14/eL14, RPL6/eL6, RPL36/eL36, FAU/RPS30-precursor/eS30 and RPL7/uL30—there is a lack of murine knockout phenotypes ( 82 ); however, they are implicated in the generation of Minute phenotypes in fruit fly ( 83 ). RPL13/eL13, at ∼80% identity between human and zebrafish presents a missense and three splice variants, the latter leading to an 18 aa insertion, with RPL13/eL13 being the cause of a rare ribosomopathy, characterized by skeletal dysplasia ( 84 ). Furthermore, RPL13/eL13 was discovered to be a candidate disease gene in patients with congenital heart disease, with heart-specific RPL13/eL13 knockdowns compromising embryonal heart development in fruit fly ( 85 ).…”

Ribosomopathies: New Therapeutic Perspectives

“…Recently, we identified de novo mutations responsible for the expression of abnormal variants of the 60S subunit protein RPL13 (eL13). These proteins are efficiently integrated, giving “mutated” ribosomes responsible for severe bone defects [ 8 ].…”

16q24.3 Microduplication in a Patient With Developmental Delay, Intellectual Disability, Short Stature, and Nonspecific Dysmorphic Features: Case Report and Review of the Literature

“…RPL13 , another gene involved in this duplication, code for a protein incorporated in the 60S subunit of ribosomes, and was very recently described by Le Caignec et al to be associated with a human ribosomopathy, Isidor-Toutain spondyloepimetaphyseal dysplasia, an autosomal dominant disorder ( 27 ). These authors showed that RPL13 gene is highly expressed in osteoblasts and chondrocytes from hypertrophic and remodeling zones in mouse growth plate ( 27 ).…”

“…RPL13 , another gene involved in this duplication, code for a protein incorporated in the 60S subunit of ribosomes, and was very recently described by Le Caignec et al to be associated with a human ribosomopathy, Isidor-Toutain spondyloepimetaphyseal dysplasia, an autosomal dominant disorder ( 27 ). These authors showed that RPL13 gene is highly expressed in osteoblasts and chondrocytes from hypertrophic and remodeling zones in mouse growth plate ( 27 ). RPL13 gene duplication is not known to be associated with human disorder, but the high RPL13 expression in bones and the association with a skeletal dysplasia in case of heterozygous splice variant could have a role for the very low bone density seen in the present case ( 27 ).…”

“…These authors showed that RPL13 gene is highly expressed in osteoblasts and chondrocytes from hypertrophic and remodeling zones in mouse growth plate ( 27 ). RPL13 gene duplication is not known to be associated with human disorder, but the high RPL13 expression in bones and the association with a skeletal dysplasia in case of heterozygous splice variant could have a role for the very low bone density seen in the present case ( 27 ). Also, it is known that RPL13 gene is a very evolutionary conserved gene and a duplication at this level might have a certain impact, that for the moment we cannot prove.…”