Ribosomal Protein S24 Gene Is Mutated in Diamond-Blackfan Anemia

Division of Genetics, Children's Hospital Boston, Boston, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2007; 79(6):1110-8. DOI: 10.1086/510020
Source: PubMed

ABSTRACT Diamond-Blackfan anemia (DBA) is a rare congenital red-cell aplasia characterized by anemia, bone-marrow erythroblastopenia, and congenital anomalies and is associated with heterozygous mutations in the ribosomal protein (RP) S19 gene (RPS19) in approximately 25% of probands. We report identification of de novo nonsense and splice-site mutations in another RP, RPS24 (encoded by RPS24 [10q22-q23]) in approximately 2% of RPS19 mutation-negative probands. This finding strongly suggests that DBA is a disorder of ribosome synthesis and that mutations in other RP or associated genes that lead to disrupted ribosomal biogenesis and/or function may also cause DBA.

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Available from: Jeffrey Lipton, Sep 26, 2015
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    • "In zebrafish and mice, reduced ribosomal protein function results in defects affecting brain, skeleton, eye, and ear development (Amsterdam et al., 2004; Oliver et al., 2004; Uechi et al., 2006; McGowan et al., 2008; Kondrashov et al., 2011; Watkins-Chow et al., 2013). In humans, Diamond-Blackfan anemia and isolated congenital asplenia are associated with mutations in ribosomal proteins (Draptchinskaia et al., 1999; Willig et al., 1999; Gazda et al., 2006, 2008; Farrar et al., 2008; Bolze et al., 2013). Different models have been proposed to explain ribosomal protein mutant phenotypes, including ribosome heterogeneity, extraribosomal function, and targeting of specific transcripts for translational regulation (Byrne, 2009; Warner and McIntosh, 2009; Horiguchi et al., 2012; Xue and Barna, 2012). "
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    ABSTRACT: Ribosomal protein mutations in Arabidopsis thaliana result in a range of specific developmental phenotypes. Why ribosomal protein mutants have specific phenotypes is not fully known but such defects potentially result from ribosome insufficiency, ribosome heterogeneity or extra-ribosomal functions of ribosomal proteins. Here, we report that ovule development is sensitive to the level of ribosomal protein RPL27a, and is disrupted by mutations in the two paralogs RPL27aC and RPL27aB. Mutations in RPL27aC result in high levels of female sterility, whereas mutations in RPL27aB have a significant but lesser effect on fertility. Progressive reduction in RPL27a function results in increasing sterility indicating a dose-dependent relationship between RPL27a and female fertility. RPL27a levels in both the sporophyte and gametophyte affect female gametogenesis with different developmental outcomes determined by the dose of RPL27a. These results demonstrate RPL27aC and RPL27aB act redundantly and reveal a function for RPL27a in coordinating complex interactions between sporophyte and gametophyte during ovule development.
    Plant physiology 05/2014; 165(3). DOI:10.1104/pp.114.241778 · 6.84 Impact Factor
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    • "The ribosomal subunit 14 gene (RPS14), located within the distal CDR, is essential for the assembly of ribosomal complexes that translate mRNA into proteins. Several lines of direct and indirect evidence strongly implicate RPS14 in the pathogenesis of del(5q) MDS: (1) inactivating mutations of other ribosomal proteins have been linked with congenital BM failure syndromes such as Diamond–Blackfan anemia [18]; (2) systematic experimental knockdown of CDR genes in normal human CD34+ cells by RNA interference (RNAi) indicated that only the knockdown of RPS14 suppressed erythroblast proliferation and viability, without a significant impact on thrombopoiesis [19]; (3) forced expression of RPS14 in CD34+ cells from patients with del(5q) MDS restored normal erythropoiesis [19];(4) haploinsufficiency of the RPS14 region in a mouse model led to a “5q– syndrome” MDS-like phenotype with macrocytic anemia and monolobulated megakaryocytes; [20] however, these mice did not demonstrate thrombocytosis or neutropenia, suggesting the involvement of distinct haploinsufficient genes in the myeloid and megakaryocyte abnormalities that are characteristic of del(5q) MDS. Experimental evidence indicates that haploinsufficiency of RPS14 upregulates the p53 pathway, a key pathway that induces cell cycle arrest and apoptosis, specifically in erythroid cells, leading to hypoplastic anemia [17, 21]. "
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    ABSTRACT: Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, >5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians' ability to predict/monitor response and identify patients at risk of relapse.
    Annals of Hematology 09/2013; 93(1). DOI:10.1007/s00277-013-1863-5 · 2.63 Impact Factor
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    • "Furthermore, by causing craniofacial anomalies if mutated, Pak1ip1 joins a group of molecules causative in ribosomopathies associated with craniofacial defects. They include for instance TCOF1 (Treacher-Collins-Franceschetti syndrome 1) and ribosomal proteins S19 and S24 (RPS19, RPS24) in Diamond-Blackfan anemia [21], [22]. "
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    ABSTRACT: Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.
    PLoS ONE 07/2013; 8(7):e69333. DOI:10.1371/journal.pone.0069333 · 3.23 Impact Factor
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