Diamond Blackfan Anemia at the Crossroad between Ribosome Biogenesis and Heme Metabolism
نویسندگان
چکیده
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.
منابع مشابه
Ribosomopathies: human disorders of ribosome dysfunction.
Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome bioge...
متن کاملEnhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.
BACKGROUND Diamond-Blackfan anemia is a fatal congenital anemia characterized by a specific disruption in erythroid progenitor cell development. Approximately 25% of patients have mutations in the ribosomal protein RPS19 suggesting that Diamond-Blackfan anemia may be caused by a defect in ribosome biogenesis and translation. However, it is unclear how these defects specifically disrupt early er...
متن کاملSpecific Role for Yeast Homologs of the Diamond Blackfan Anemia-associated Rps19 Protein in Ribosome Synthesis.
Approximately 25% of cases of Diamond Blackfan anemia, a severe hypoplastic anemia, are linked to heterozygous mutations in the gene encoding ribosomal protein S19 that result in haploinsufficiency for this protein. Here we show that deletion of either of the two genes encoding Rps19 in yeast severely affects the production of 40 S ribosomal subunits. Rps19 is an essential protein that is stric...
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Hereditary forms of bone marrow failure and aplastic anaemia (AA) manifest in rare blood syndromes (Dyskeratosis Congenita, Diamond-Blackfan Anaemia and Shwachman-Diamond Syndrome) in which genetic abnormalities directly impair ribosome biogenesis. These conditions are all associated with varying degrees of predisposition to haematological malignancy. Various studies of ribosome proteins have r...
متن کاملMutation of ribosomal protein RPS24 in Diamond-Blackfan anemia results in a ribosome biogenesis disorder.
Diamond-Blackfan anemia (DBA) is a rare congenital disease affecting erythroid precursor differentiation. DBA is emerging as a paradigm for a new class of pathologies potentially linked to disorders in ribosome biogenesis. Three genes encoding ribosomal proteins have been associated to DBA: after RPS19, mutations in genes RPS24 and RPS17 were recently identified in a fraction of the patients. H...
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عنوان ژورنال:
دوره 2010 شماره
صفحات -
تاریخ انتشار 2010