Mutations in ribosomal protein S19 gene and Diamond Blackfan anemia: Wide variations in phenotypic expression

Mutations of the ribosomal protein S19 (RPS19) gene were recently identifie d in 10 patients with Diamond Blackfan anemia (DBA). To determine the preva lence of mutations in this gene in DBA and to begin to define the molecular basis for the observed variable clinical phenotype of this disorder, the g enomic sequence of the 6 exons and the 5' untranslated region of the RPS19 gene was directly assessed in DBA index cases from 172 new families. Mutati ons affecting the coding sequence of RPS19 or splice sites were found in 34 cases (19.7%), whereas mutations in noncoding regions were found in 8 pati ents (4.6%). Mutations included nonsense, missense, splice sites, and frame shift mutations. A hot spot for missense mutations was identified between c odons 52 and 62 of the RPS19 gene in a new sequence consensus motif W-[YFW] [YF]-x-R-[AT]-A-[SA]-x-[AL]-R-[HRK]-[ILV]-Y. No correlation between the nat ure of mutations and the different patterns of clinical expression, includi ng age at presentation, presence of malformations, and therapeutic outcome, could be documented. Moreover, RPS19 mutations were also found in some fir st-degree relatives presenting only with isolated high erythrocyte adenosin e deaminase activity and/or macrocytosis. The lack of a consistent relation ship between the nature of the mutations and the clinical phenotype implies that yet unidentified factors modulate the phenotypic expression of the pr imary genetic defect in families with RPS19 mutations. (C) 1999 by The Amer ican Society of Hematology.