Analysis of the X-Linked F-Cell Production Locus.

This laboratory has previously identified a locus on the X chromosome at Xp22.2–22.3 (F-cell production locus or FCP) that is responsible for approximately 40% of the genetic variability in F-cell number in patients with sickle cell disease (SCD). We have re-examined the association of this region with F-cell production by multipoint linkage analysis. We have confirmed linkage to Xp22.2–22.3 and refined the candidate locus to a region of approximately 3 cM, between markers DXS452 and DXS410, with a maximum LOD score of 3.315. Linkage to a more extended region of 11 cM with an average LOD score of 1.5 could not be excluded. In an effort to identify candidate genes within this region that influence F-cell production, we screened known genes within this region for transcription factor binding sites that had relevance to HbF production. We first searched for CREB binding sites given the involvement of cAMP in of HbF induction in CD34 cells recently identified by this laboratory. Of the 15 ESTs containing CREB sequences, several also had binding sites for NFE2 or NFE2-like transcription factors. We examined 4 genes, 3 within the refined candidate locus (KIAA1280, TBL1X, and KAL1) and one in the more extended locus region (EGFL6) for expression levels within pedigrees of known F-cell phenotypes. Results indicate that, within families, a reduced level of KIAA1280 message is associated with high F-cell phenotypes in lymphoblastoid cells from patients with sickle cell anemia. The other genes examined had no such correlation.

KIAA1280, also designated BMO42 is a gene of unknown function that is expressed in bone marrow. The predicted protein contains a region homologous to a conserved protein kinase C domain. While not yet definitive, these studies provide the first suggestive evidence for a candidate gene within the FCP locus. Further studies will attempt to define the function of this gene and explore it’s involvement in F-cell regulation.