Isolation and sequence of two genes associated with a CpG island 5' of the factor VIII gene.

Many disease loci have been linked to the telomeric end of the long arm of the human X-chromosome, Xq28. We have isolated and sequenced cDNA sequences corresponding to two novel genes that map to Xq28. These genes, c6.1A and c6.1B, are transcribed in opposite directions from a CpG island that lies approximately 70 kilobases (kb) upstream (5') of the factor VIII locus. One of these genes, c6.1A, is highly conserved between species and expressed abundantly in many human and mouse tissues, whereas, c6.1B is moderately conserved and has a restricted tissue distribution of expression. The Xq28 gene c6.1A has an autosomal homologue that is transcriptionally inactive in B-cell lines. An open reading frame (ORF) predicting a peptide of 293 amino acids is observed for c6.1A but c6.1B does not possess a single long ORF. No striking homologies to existing genes could be found for either of the two new loci. Expressed sequences that are physically close to the factor VIII gene are candidates for disease loci that map to this region of Xq28. The relevance of these genes to disease loci was investigated using DNA and RNA from hemophilia A patients bearing deletions that extend in a 5' direction away from factor VIII. The results imply that neither of these genes are primarily responsible for the development Xq28-linked diseases. However, c6.1A and c6.1B define a region of Xq28 that is deleted in two brothers that suffer from mental handicap and dysmorphism as well as hemophilia A. Thus, this region is likely to contain loci that are important for physical and mental development.