Expression of human F8B, a gene nested within the coagulation factor VIII gene, produces multiple eye defects and developmental alterations in chimeric and transgenic mice

Factor VIII-associated gene B (F8B) is a small human gene of unknown functi on which is nested within the gene encoding coagulation foactor VIII (FVIII ) in chromosome band Xq28, The sequence of F8B includes the C2 cell adhesio n motif of factor VIII, which has also been identified in numerous proteins known to play important roles during development, Here we have constructed both chimeric and transgenic mice expressing normal human F8B to investiga te its possible developmental effects, The chimeras produced from embryonic stem cells transfected with normal F8B under control of a cytomegalovirus promoter and selected for neomycin resistance expressed readily detectable levels of F8B mRNA in multiple tissues. They showed growth retardation, mic rocephaly, reduced longevity and severe ocular defects, and although they w ere fertile, gave birth to no F8B heterozygous pups. Seven transgenic mouse lines, produced by injection of the transgene into fertilized oocytes, wer e viable and of normal size but expressed lower levels of F8B mRNA, Strikin gly, they showed the same severe eye abnormalities as the chimeras. These d efects included anterior segment dysgenesis, absent or abnormal lens, persi stence of the primary vitreous, Harderian gland tumors and ectopic pigmente d cells, suggesting that migration of neural crest cells might have been pe rturbed during eye development. In addition, dysplastic retinas and the abs ence of photoreceptors were observed, providing a mouse model for retinal d egeneration.