RPS19 mutations in patients with Diamond-Blackfan anemia

Abstract

Communicated by Maria Rita Passos-BuenoDiamond-Blackfan anemia (DBA) is an inherited disease characterized by pure erythroid aplasia. Thirty percent (30%) of patients display malformations, especially of the hands, face, heart, and urogenital tract. DBA has an autosomal dominant pattern of inheritance. De novo mutations are common and familial cases display wide clinical heterogeneity. Twenty-five percent (25%) of patients carry a mutation in the ribosomal protein (RP) S19 gene, whereas mutations in RPS24, RPS17, RPL35A, RPL11, and RPL5 are rare. These genes encode for structural proteins of the ribosome. A link between ribosomal functions and erythroid aplasia is apparent in DBA, but its etiology is not clear. Most authors agree that a defect in protein synthesis in a rapidly proliferating tissue, such as the erythroid bone marrow, may explain the defective erythropoiesis. A total of 77 RPS19 mutations have been described. Most are whole gene deletions, translocations, or truncating mutations (nonsense or frameshift), suggesting that haploinsufficiency is the basis of DBA pathology. A total of 22 missense mutations have also been described and several works have provided in vitro functional data for the mutant proteins. This review looks at the data on all these mutations, proposes a functional classification, and describes six new mutations. It is shown that patients with RPS19 mutations display a poorer response to steroids and a worse long-term prognosis compared to other DBA patients. Hum Mutat 29(7), [911][912][913][914][915][916][917][918][919][920] 2008.

Identification of mutations in the ribosomal protein L5 (RPL5) and ribosomal protein L11 (RPL11) genes in Czech patients with Diamond-Blackfan anemia

“…All have flat thenar and some also have bifid thumb, while no thumb anomalies are observed in patients with RPS19 mutations. This is also in agreement with a recently published review of genetic and clinical data for 104 patients with RPS19 mutations, in which only 31% of patients have associated anomalies: nine patients (8.7%) were reported to have thumb anomalies, and only one had flat thenar (1%) [Campagnoli et al, 2008]. Interestingly, flat thenar was also observed in both patients with an RPL11 mutation and in one patient with an RPS17 mutation, indicating that these RPs are in some way more important for proper thumb development than RPS19.…”

Ribosomopathies: human disorders of ribosome dysfunction

“…16 This suggests that haploinsufficiency for a ribosomal gene in the nucleolus is the basis for the pathology. 78 Cmejlova et al showed that the level of translation was on average 48% to 73% of controls in both unstimulated and phytohemagglutinin-stimulated DBA lymphocytes irrespective of mutations in RPS19. 79 In the DBA patients who have been found to have RPL35A mutations, haploinsufficiency of RPL35A is inferred based on genomic deletions or a nonsense splicing defect in 1 allele.…”

“…78 The majority are whole gene deletions, translocations, or truncating mutations (nonsense or frameshift) universally present in only a single allele. 16,78 One group of missense mutations in RPS19 alters the nucleolar localization signal with a resulting dramatic decrease in protein expression. 16 This suggests that haploinsufficiency for a ribosomal gene in the nucleolus is the basis for the pathology.…”

Anémie de Diamond-Blackfan

“…Les mutations répertoriées dans le gène le plus fréquemment muté, RPS19, Incorporation dans les pré-ribosomes affectent la région promotrice, les séquences introniques et l'ensemble de la séquence codante : mutations faux-sens, non-sens, insertions, délétions [28]. Si certaines de ces mutations aboutissent clairement à un allèle nul, l'impact des nombreuses mutations ponctuelles faux-sens est plus difficile à évaluer a priori.…”