ORPHA: 124; DO: 0111882;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p24.2 | Diamond-Blackfan anemia 12 | 615550 | Autosomal dominant | 3 | RPL15 | 604174 |
A number sign (#) is used with this entry because of evidence that Diamond-Blackfan anemia-12 (DBA12) is caused by heterozygous mutation in the RPL15 gene (604174) on chromosome 3p24.
Diamond-Blackfan anemia (DBA) is an inherited red blood cell aplasia that usually presents in the first year of life. The main features are normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. Patients show growth retardation, and approximately 30 to 50% have craniofacial, upper limb, heart, and urinary system congenital malformations. The majority of patients have increased mean corpuscular volume, elevated erythrocyte adenosine deaminase activity, and persistence of hemoglobin F. However, some DBA patients do not exhibit these findings, and even in the same family, symptoms can vary between affected family members (summary by Landowski et al., 2013).
For a discussion of genetic heterogeneity of DBA, see DBA1 (105650).
Landowski et al. (2013) reported a patient (P1) with Diamond-Blackfan anemia and a mutation in the RPL15 gene. She was diagnosed with anemia at birth, responded to corticosteroid treatment, and was in remission for the past 6 years. She had a ventricular septal defect and triphalangeal thumbs.
Wlodarski et al. (2018) reported 6 unrelated patients with DBA12. All 6 patients presented with bone marrow erythroid hypoplasia and elevated erythrocyte adenosine deaminase levels, and most of the patients had increased fetal hemoglobin levels. Three of the patients had hydrops fetalis. One of the patients (patient 2) also had an intermittent cardiac atrioventricular block, duplex left kidney, hypogonadism, ambiguous genitalia, microcephaly, left cerebellar hypoplasia, developmental delay, and cerebral palsy. Another patient (patient 6) had growth retardation and impaired intellectual development.
Landowski et al. (2013) studied 87 probands diagnosed with DBA on the basis of normochromic, often macrocytic anemia; reticulocytopenia; a low number or lack of erythroid precursors in bone marrow; and, in some patients, congenital malformations and elevated erythrocyte adenosine deaminase activity. All patients had previously been screened by Sanger sequencing and were negative for mutation in the 10 DBA-associated ribosomal protein genes; array CGH for copy number variation revealed large deletions in 6 probands, including 1 in the RPL15 gene (604174.0001) in proband 1 (P1).
Wlodarski et al. (2018) identified heterozygous nonsense and missense mutations in the RPL15 gene in 6 unrelated patients with DBA12 (604174.0002-604174.0005). One of the nonsense mutations (Y81X; 604174.0002) was found in 3 patients. The mutations were identified by Sanger sequencing of the RPL15 gene in a cohort of 985 patients with DBA without a molecular diagnosis. In lymphoblastoid cells from 2 of the patients with the Y81X mutation, impaired pre-rRNA processing, decreased 60S ribosomal subunit formation, and deficient cell proliferation were identified. Bone marrow mononuclear cells from these 2 patients also showed increased TP53-induced apoptosis and increased p21 mRNA and delayed erythrocyte maturation compared to wildtype cells.
Wlodarski et al. (2018) identified heterozygous nonsense mutations in the RPL15 gene in 4 unrelated patients with DBS12, including 3 with Y81X (604174.0002) and 1 with Q29X (604174.0003). Three of these patients had hydrops fetalis, which is a rare presentation in DBA. The 3 patients with the Y81X mutation achieved rapid treatment independence, both with or without steroid therapy. This treatment independence was not due to gene mutation reversion.
Landowski, M., O'Donohue, M.-F., Buros, C., Ghazvinian, R., Montel-Lehry, N., Vlachos, A., Sieff, C. A., Newburger, P. E., Niewiadomska, E., Matysiak, M., Glader, B., Atsidaftos, E., Lipton, J. M., Beggs, A. H., Gleizes, P.-E., Gazda, H. T. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum. Genet. 132: 1265-1274, 2013. [PubMed: 23812780] [Full Text: https://doi.org/10.1007/s00439-013-1326-z]
Wlodarski, M. W., Da Costa, L., O'Donohue, M. F., Gastou, M., Karboul, N., Montel-Lehry, N., Hainmann, I., Danda, D., Szvetnik, A., Pastor, V., Paolini, N., di Summa, F. M., Tamary, H., Quider, A. A., Aspesi, A., Houtkooper, R. H., Leblanc, T., Niemeyer, C. M., Gleizes, P. E., MacInnes, A. W. Recurring mutations in RPL15 are linked to hydrops fetalis and treatment independence in Diamond-Blackfan anemia. Haematologica 103: 949-958, 2018. [PubMed: 29599205] [Full Text: https://doi.org/10.3324/haematol.2017.177980]