Diamond-Blackfan Anemia 3

A number sign (#) is used with this entry because Diamond-Blackfan anemia-3 (DBA3) is caused by heterozygous mutation in the ribosomal protein S24 gene (RPS24; 602412) on chromosome 10q22.

Description

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 Diamond-Blackfan anemia, see DBA1 (105650).

Mapping

Gazda et al. (2006) performed a genomewide linkage screen on an extensive family with Diamond-Blackfan anemia. The found evidence for linkage to a 5.8-Mb region on chromosome 10 as well as to regions on chromosomes 8q (17.5 Mb) and 6 (3.8 Mb).

Molecular Genetics

In affected members of a family segregating Diamond-Blackfan anemia, Gazda et al. (2006) detected no mutations in the RPS20 (603682) or RPL7 (604166) genes in the critical region on 8q, but they identified a heterozygous nonsense mutation in exon 4 of the RPS24 gene on chromosome 10q22-q23 (602412.0001). Gazda et al. (2006) subsequently sequenced RPS24 in 185 unrelated probands with DBA, representing both familial and sporadic cases. They found another nonsense mutation in exon 2 in a transfusion-dependent patient (602412.0002), and a deletion/insertion mutation at the intron 1/exon 2 boundary in a steroid-dependent patient and his father (602412.0003). The father did not have any signs of anemia at that time; however, during childhood he presented with multiple heart anomalies, elevated erythrocyte adenosine deaminase activity (eADA), and moderate anemia, which was resistant to iron treatment and at that time was attributed to his cardiac abnormalities. No RPS24 mutation was found among 210 control individuals. Gazda et al. (2006) concluded that the RPS24 gene is mutated in approximately 2% of RPS19 (603474) mutation-negative DBA probands.

Landowski et al. (2013) performed array CGH for copy number variation in 87 probands with Diamond-Blackfan anemia who were negative for mutation in 10 known DBA-associated ribosomal protein genes and identified a large de novo deletion in the RPS24 gene (602412.0004) in a steroid-dependent male patient.

Pathogenesis

Choesmel et al. (2008) found that lymphoblastoid cells derived from DBA3 patients with RPS24 mutations (602412.0001-612412.0003) had altered pre-rRNA processing, with lower levels of 41S pre-rRNA and accumulation of the 30S species, resulting in a lower 41S/30S ratio compared to that in controls. There was also less 21S and 18S-E pre-rRNA compared to controls, but the 21S/18S-E ratio was similar to that in controls. HeLa cells with siRNA against RPS24 showed a loss of free 40S ribosomal subunits and an accumulation of 60S subunits, indicating that RPS24 is essential for the production of the small ribosomal subunit 40S. Pulse-chase labeling and Northern blot studies of siRNA-knockdown cells showed lack of formation of 41S, 21S, and 18S-E pre-rRNA, although 28S was normal and 30S was increased. These findings suggested inhibition of cleavage at the 5-prime external transcribed spacer (ETS), as well as blocking of the subsequent processing of internal spacer-1 (ITS1) at the 3-prime end of the 18S rRNA. The pattern of the 60S rRNA subunit was normal, as were patterns of 28S and 5.8S rRNAs. RPS19 was also decreased, likely due to impaired synthesis of the 40S subunit. The pattern resulting from RPS24 depletion was similar to that of RPS19 depletion, in that depletion of RPS19 results in delayed maturation of the 40S subunit (Flygare et al., 2007). However, RPS19 depletion resulted in increased 41S and 21S pre-rRNAs levels, consistent with a defect in processing at ITS1. Studies combining deletions of RPS24 and RPS19 indicated that the 2 exert interdependent functions in pre-rRNA processing. Choesmel et al. (2008) concluded that mutations in the RPS24 gene result in haploinsufficiency, and that the pathogenesis of DBA is related to defective ribosome biogenesis, which may result in apoptosis of rapidly proliferating cells such as erythroid precursors.