Fibroblasts from patients with Diamond-Blackfan anaemia show abnormal expression of genes involved in protein synthesis, amino acid metabolism and cancer

To evaluate the involvement of non-haematopoietic tissues in DBA, we have analysed global gene expression in fibroblasts from DBA patients compared to healthy controls. Microarray expression profiling using Affymetrix GeneChip Human Genome U133A 2.0 Arrays revealed that 421 genes are differentially expressed in DBA patient fibroblasts. These genes include a large cluster of ribosomal proteins and factors involved in protein synthesis and amino acid metabolism, as well as genes associated to cell death, cancer and tissue development.This analysis reports for the first time an abnormal gene expression profile in a non-haematopoietic cell type in DBA. These data support the hypothesis that DBA may be due to a defect in general or specific protein synthesis.Protein synthesis is essential to the survival and growth of cells. Ribosomes, the sites where translation occurs, therefore play a fundamental role in cell biology. In human cells, ribosome biogenesis occurs in the nucleolus: it requires the transcription of four ribosomal RNA (rRNA) species and their assembly with 79 ribosomal proteins (RPs) in order to produce the small (40S) and large (60S) ribosomal subunits. These subunits are independently exported to the cytoplasm and joined to obtain mature ribosomes [1].Several inherited or acquired bone marrow failure syndromes are due to mutations in genes encoding proteins involved in ribosome biogenesis. They include Diamond-Blackfan anaemia (DBA, MIM#105650), Shwachman-Diamond syndrome (SDS, MIM#260400), dyskeratosis congenita (DC, MIM#127550, #305000, #224230) and 5q- syndrome (MIM#153550) [2,3]. DBA is an inherited erythroid hypoplasia which usually develops within the first year of life and is characterised by a severe normochromic macrocytic anaemia caused by a defect in the maturation of erythroid progenitors. Haematological signs include paucity of bone marrow progenitors, reticulocytopenia, elevated erythrocyte adenosine deaminase (eADA) activity and high levels