Abstract
Diamond–Blackfan anemia (DBA) is a rare genetic hypoplasia of erythroid progenitors characterized by mild to severe anemia and associated with congenital malformations. Clinical manifestations in DBA patients are quite variable and genetic testing has become a critical factor in establishing a diagnosis of DBA. The majority of DBA cases are due to heterozygous loss‐of‐function mutations in ribosomal protein (RP) genes. Causative mutations are fairly straightforward to identify in the case of large deletions and frameshift and nonsense mutations found early in a protein coding sequence, but diagnosis becomes more challenging in the case of missense mutations and small in‐frame indels. Our group recently characterized the phenotype of lymphoblastoid cell lines established from DBA patients with pathogenic lesions in RPS19 and observed that defective pre‐rRNA processing, a hallmark of the disease, was rescued by lentiviral vectors expressing wild‐type RPS19. Here, we use this complementation assay to determine whether RPS19 variants of unknown significance are capable of rescuing pre‐rRNA processing defects in these lymphoblastoid cells as a means of assessing the effects of these sequence changes on the function of the RPS19 protein. This approach will be useful in differentiating pathogenic mutations from benign polymorphisms in identifying causative genes in DBA patients.
Highlights
Diamond–Blackfan anemia (DBA) is a congenital disorder of the bone marrow characterized by normochromic macrocytic anemia and associated with physical malformations and increased risk of malignancies (Lipton & Ellis, 2009; Vlachos et al, 2008)
We reviewed the literature to collect additional RPS19 mutations identified more recently and have a total of 165 different RPS19 mutations reported in 313 DBA patients (Arbiv et al, 2017; Chae et al, 2010, 2014; Da Costa et al, 2013; Delaporta et al, 2014; Errichiello et al, 2017; Farrar et al, 2011; Gerrard et al, 2013; Ichimura et al, 2017; Konno et al, 2010; Kuramitsu et al, 2012; Landowski et al, 2013; Ozono et al, 2016; Pospisilova et al, 2012; Quarello et al, 2012; Smetanina et al, 2015; Solomon et al, 2014; Tsangaris et al, 2011; van Dooijeweert et al, 2017; Wang et al, 2015; Zhang et al, 2016)
We selected only those variants for which there was no strong evidence of pathogenicity according to the genetic criteria outlined in Materials and Methods, and obtained 47 variants of unknown significance (VUS) reported in 122 patients (39% of RPS19-mutated patients, approximately 10% of all DBA patients)
Summary
Diamond–Blackfan anemia (DBA) is a congenital disorder of the bone marrow characterized by normochromic macrocytic anemia and associated with physical malformations and increased risk of malignancies (Lipton & Ellis, 2009; Vlachos et al, 2008). DBA is usually caused by heterozygous mutations in ribosomal protein (RP) genes that lead to haploinsufficiency. Mutations in 19 RP genes (RPS19, RPS24, RPS17, RPL35A, RPL5, RPL11, RPS7, RPS10, RPS26, RPL26, RPL15, RPL31, RPS29, RPS28, RPL27, RPS27, RPS15A, RPL35, RPL18) have been.
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