Evidence for a second diamond-blackfan anemia gene on human chromosome 8p23-22, and for at least one other dba gene

Abstract

Abstract Diamond-Blackfan Anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy and is inherited in 10–20% of cases. Recently, identification of a patient with a translocation t(X;19)(p21;q13) led to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, mutations of RPS19 have only been identified in 25% of 19q-linked and sporadic cases, suggesting a greater degree of genetic heterogeneity in DBA we carried out linkage analysis and searched for RPS19 mutations in 38 multiplex families. Although approximately 40% of families were consistent for linkage to the 19q13.2 region, mutation analysis revealed mutations in only 3 families. Three different missense mutations were identified; 2 of them, in exon 4 (G185A;R62Q) and in exon 5 (T395G;L131R), are novel mutations, while the third, in exon 3 (G171A;R56Q) has been described. We excluded these kindreds from further linkage analysis. A genome-wide search for loci linked to the DBA phenotype suggested the presence of a second DBA locus on chromosome 8p. To define the critical interval more precisely we used additional polymorphic markers on chromosome 8p and applied GENEHUNTER program for calculation of parametric two-and multipoint LOD scores with heterogeneity (HLOD). A significant HLOD score (higher than 3.3 with 49% families linked to the locus) was found for the 8.1cM 8p telomeric region flanked by D8S518 and D8S1825. Six of 35 families were not consistent for linkage either to 19q or 8p, which strongly suggested further genetic heterogeneity. In conclusion, our results show evidence of a second DBA gene on 8p 23.3-22, most likely within an 8.1cM interval flanked by D8S1825 and D8S518, and also provides further support for the existence of at least one additional gene locus.