Identification of novel mutations in patients with Diamond‐Blackfan anemia and literature review of RPS10 and RPS26 mutations

Abstract

IntroductionDiamond‐Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by erythroid aplasia, physical malformation, and cancer predisposition. Twenty ribosomal protein genes and three non‐ribosomal protein genes have been identified associated with DBA.MethodsTo investigate the presence of novel mutations and gain a deeper understanding of the molecular mechanisms of disease, targeted next‐generation sequencing was performed in 12 patients with clinically suspected DBA. Literatures were retrieved with complete clinical information published in English by November 2022. The clinical features, treatment, and RPS10/RPS26 mutations were analyzed.ResultsAmong the 12 patients, 11 mutations were identified and 5 of them were novel (RPS19, p.W52S; RPS10, p.P106Qfs*11; RPS26, p.R28*; RPL5, p.R35*; RPL11, p.T44Lfs*40). Including 2 patients in this study, 13 patients with RPS10 mutations and 38 patients with RPS26 mutations were reported from 4 and 6 countries, respectively. The incidences of physical malformation in patients with RPS10 and RPS26 mutations (22% and 36%, respectively) were lower than the overall incidence in DBA patients (~50%). Patients with RPS26 mutations had a worse response rate of steroid therapy than RPS10 (47% vs. 87.5%), but preferred RBC transfusions (67% vs. 44%, p = 0.0253).ConclusionOur findings add to the DBA pathogenic variant database and demonstrate the clinical presentations of the DBA patients with RPS10/RPS26 mutations. It shows that next‐generation sequencing is a powerful tool for the diagnosis of genetic diseases such as DBA.

Ribosomal Biogenesis and Heterogeneity in Development, Disease, and Aging

“…A large set of RPs are associated with a rare congenital disorder called Diamond–Blackfan anaemia, in which bone marrow failure causes a spectrum of pathologies including normochromic and macrocytic anaemia; reticulocytopenia; a near absence of erythroid progenitors in the bone; slow growth and reduced height; microcephaly and micrognathia (smaller head and lower jaw, respectively); and malformation of the upper limb, heart, and urinary systems [ 54 ]. Our review of the literature lists 29 RPs along with one ribosome-related protein called TSR2 ribosome maturation factor (TSR2) and three non-ribosomal proteins, namely, hematopoietic master transcription factor GATA1, erythropoietin (EPO), and adenosine deaminase 2 (ADA2), associated with this disease [ 55 ] ( Table 2 ). Other ribosomopathies include refractory macrocytic anaemia (RPS14), autism/neurodevelopment disorder (RPL10), asplenia (RPSA), brachycephaly, trichomegaly and development delay (RPS23), spondyloepimetaphyseal dysplasia (poor bone growth) (RPL13), and hypotrichosis (poor hair growth) (RPL21) [ 37 ].…”

Ribosomal composition affects the noncanonical translation and toxicity of polyglycine-containing proteins in fragile X-associated conditions

“…Therefore, the activity of this chaperon may play an important role in modulating RAN translation via Rps26 assembly or disassembly from ribosomal subunits, also during different stresses (Yang & Karbstein, 2022). Moreover, mutations in genes encoding RPS26 and TSR2 were associated with hematopoiesis impairment that underlies the genetic blood disorder Diamond-Blackfan anemia (DBA) (Piantanida et al, 2022;Li et al, 2023;Doherty et al, 2010). Previously, analyses of DBA patient cells and RPS26-depleted HeLa cells found alterations in ribosome biogenesis and pre-rRNA processing (Doherty et al, 2010).…”