Human Molecular Genetics, 1999, Vol. 8, No. 7 1291-1301
© 1999 Oxford University Press
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
1Laboratoire de Biologie Moléculaire des Cellules Eucaryotes EA 1501, 3Laboratoire de Génétique Physiologique INSERM U257 and 4Service de Radiologie, Université Paris V, Faculté de Médecine Cochin-Port-Royal, 24, rue du Fauberg St Jacques, 75014 Paris cédex 05, France and 2Laboratoire du Dévelopement, Vieillissement et Pathologie de la Rétine INSERM U450, 29, rue Wilhem, 75016 Paris, France
Factor VIII-associated gene B (F8B) is a small human gene of unknown function which is nested within the gene encoding coagulation foactor VIII (FVIII ) in chromosome band Xq28. The sequence of F8B includes the C2 cell adhesion 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 investigate 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, microcephaly, reduced longevity and severe ocular defects, and although they were fertile, gave birth to no F8B heterozygous pups. Seven transgenic mouse lines, produced by injection of the transgene into fertilized oocytes, were viable and of normal size but expressed lower levels of F8B mRNA. Strikingly, they showed the same severe eye abnormalities as the chimeras. These defects included anterior segment dysgenesis, absent or abnormal lens, persistence of the primary vitreous, Harderian gland tumors and ectopic pigmented cells, suggesting that migration of neural crest cells might have been perturbed during eye development. In addition, dysplastic retinas and the absence of photoreceptors were observed, providing a mouse model for retinal degeneration.
a To whom correspondence should be addressed. Tel: +33 1 42 34 19 20; Fax: +33 1 44 41 15 22; Email: delpech{at}icgm.cochin.inserm.fr
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