title: Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline.
abstract: Choroideremia (CHM) is an X-linked progressive eye disorder which results from defects in the human Rab escort protein-1 (REP-1) gene. A gene targeting approach was used to disrupt the mouse chm/rep-1 gene. Chimeric males transmitted the mutated gene to their carrier daughters but, surprisingly, these heterozygous females had neither affected male nor carrier female offspring. The targeted rep-1 allele was detectable, however, in male as well as female blastocyst stage embryos isolated from a heterozygous mother. Thus, disruption of the rep-1 gene gives rise to lethality in male embryos; in female embryos it is only lethal if the mutation is of maternal origin. This observation can be explained by preferential inactivation of the paternal X chromosome in murine extraembryonic membranes suggesting that expression of the rep-1 gene is essential in these tissues. In both heterozygous females and chimeras the rep-1 mutation causes photoreceptor cell degeneration. Consequently, conditional rescue of the embryonic lethal phenotype of the rep-1 mutation may provide a faithful mouse model for choroideremia.
authors.affiliation: Department of Human Genetics, University Hospital Nijmegen, The Netherlands. j.vandenhurk@antrg.azn.nl
authors.forename: J A
authors.initials: JA
authors.lastname: van den Hurk
authors.forename: W
authors.initials: W
authors.lastname: Hendriks
authors.forename: D J
authors.initials: DJ
authors.lastname: van de Pol
authors.forename: F
authors.initials: F
authors.lastname: Oerlemans
authors.forename: G
authors.initials: G
authors.lastname: Jaissle
authors.forename: K
authors.initials: K
authors.lastname: Rüther
authors.forename: K
authors.initials: K
authors.lastname: Kohler
authors.forename: J
authors.initials: J
authors.lastname: Hartmann
authors.forename: E
authors.initials: E
authors.lastname: Zrenner
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: B
authors.initials: B
authors.lastname: Wieringa
authors.forename: H H
authors.initials: HH
authors.lastname: Ropers
authors.forename: F P
authors.initials: FP
authors.lastname: Cremers
mesh_terms: D019883:Alkyl and Aryl Transferases; D000818:Animals; D001757:Blastomeres; D002352:Carrier Proteins / Q000235:genetics*; D015794:Choroideremia / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D005854:Germ Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010786:Photoreceptor Cells / Q000473:pathology*; D016133:Polymerase Chain Reaction; D020691:rab GTP-Binding Proteins
chemical_list: D002352:Carrier Proteins; D019883:Alkyl and Aryl Transferases; D020691:rab GTP-Binding Proteins