LOCALIZATION OF THE GENE FOR CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE-I TO A LESS-THAN-1-CM INTERVAL ON CHROMOSOME 15Q15.1-15.3

Congenital dyserythropoietic anemias (CDA) are a rare group of red-blo od-cell disorders of unknown etiology that are characterized by ineffe ctive erythropoiesis, pathognomonic cytopathology of the nucleated red blood cells in the bone marrow, and secondary hemochromatosis. In CDA type I, bone-marrow electron microscopy reveals characteristic findin gs in erythroid precursors, including spongy heterochromatin and enlar ged nuclear pores. Since the genetic basis of CDA type I is not eviden t, we used homozygosity and linkage mapping to localize the genetic de fect responsible for CDA type I in 25 Bedouins from four large consang uineous families. We report the linkage of this disease to markers on chromosome 15 located at q15.1-q15.3. Fourteen markers within a 12-cM interval were typed in the relevant family members. Nine of the marker s yielded maximum LOD scores of 1.625-12.928 at a recombination fracti on of .00. Linkage disequilibrium was found only with marker D15S779. Haplotype analysis revealed eight different carrier haplotypes and hig hlighted the existence of a founder haplotype. Identification of histo rical crossover events further narrowed the gene location to between D 15S779 and D15S778. The data suggest localization of the CDA type I ge ne within a 0.5-cM interval. The founder mutation probably occurred gr eater than or equal to 400 years ago. Sequence analysis of the coding region of protein 4.2, the only known erythroid-specific gene in the l ocus, did not reveal any change in the CDA type I patients. Future ana lysis of this locus may lead to the identification of a gene essential to normal erythropoiesis.