Diamond Blackfan Anemia at the Crossroad between Ribosome Biogenesis and Heme Metabolism

Abstract

Diamond-Blackfan anemia (DBA) is a rare, pure red-cell aplasia that presents during infancy. Approximately 40% of cases are associated with other congenital defects, particularly malformations of the upper limb or craniofacial region. Mutations in the gene coding for the ribosomal protein RPS19 have been identified in 25% of patients with DBA, with resulting impairment of 18S rRNA processing and 40S ribosomal subunit formation. Moreover, mutations in other ribosomal protein coding genes account for about 25% of other DBA cases. Recently, the analysis of mice from which the gene coding for the heme exporter Feline Leukemia Virus subgroup C Receptor (FLVCR1) is deleted suggested that this gene may be involved in the pathogenesis of DBA. FLVCR1-null mice show a phenotype resembling that of DBA patients, including erythroid failure and malformations. Interestingly, some DBA patients have disease linkage to chromosome 1q31, where FLVCR1 is mapped. Moreover, it has been reported that cells from DBA patients express alternatively spliced isoforms of FLVCR1 which encode non-functional proteins. Herein, we review the known roles of RPS19 and FLVCR1 in ribosome function and heme metabolism respectively, and discuss how the deficiency of a ribosomal protein or of a heme exporter may result in the same phenotype.

Haplo-insufficiency for different genes differentially reduces pathogenicity and virulence in a fungal phytopathogen

“…Unlike S. cerevisiae, only 22 genes have been reported to display haplo-insufficiency in S. pombe (Baek et al, 2008). The majority of these were ribosomal proteins, an interesting parallel with what is observed in the human disorder, DBA (Chiabrando and Tolosano, 2010). Interestingly, in the human pathogen C. albicans, 146 genes that regulate yeastto-hyphae transition display dosage-dependent activity (Uhl et al, 2003).…”

“…For example, genes that code for transcription factors (TWIST and GATA3), DNA helicase (BLM), and DNA repair proteins (ATM) have been shown to display haplo-insufficiency (Deutschbauer et al, 2005). Lossof-function of an allele for genes that display haplo-insufficiency had been shown to translate into diseases such as Marfan syndrome, cancer (Baek et al, 2008), pulmonary arterial hypertension (Huang et al, 2010) and Diamond Blackfan anemia (DBA) (Chiabrando and Tolosano, 2010). However, haplo-insufficiency has only been described in three species of fungi.…”

Control of intracellular heme levels: Heme transporters and heme oxygenases

“…Mutations of ribosomal proteins (notably RPS19, 24 and 17) are seen in approximately 45% of patients with DBA (reviews, [208, 209]). Mutation of RPS19 results in defective maturation of the 40S (translation initiation) ribosomal subunit [210], whereas RPS24 and 17 are also associated with the 40S subunit [202].…”

Placental Expression of the Heme Transporter, Feline Leukemia Virus Subgroup C Receptor, Is related to Maternal Iron Status in Pregnant Adolescents

“…These findings suggest that FLVCR1 may control intracellular heme content as heme synthesis increases to support erythrocyte differentiation (17). FLVCR1 may also play a role in the etiology of Diamond Blackfan Anemia (a congenital human pure red-cell aplasia) (18,19). Recently, FLVCR2 was also identified as a cell surface heme transporter, but at present much less is known about this FLVCR1 homolog (20).…”