Mouse choroideremia gene mutation causes photoreceptor cell degeneration and is not transmitted through the female germline.
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.
van den Hurk
J A
JA
Department of Human Genetics, University Hospital Nijmegen, The Netherlands. j.vandenhurk@antrg.azn.nl
Hendriks
W
W
van de Pol
D J
DJ
Oerlemans
F
F
Jaissle
G
G
Rüther
K
K
Kohler
K
K
Hartmann
J
J
Zrenner
E
E
van Bokhoven
H
H
Wieringa
B
B
Ropers
H H
HH
Cremers
F P
FP
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
D002352:Carrier Proteins; D019883:Alkyl and Aryl Transferases; D020691:rab GTP-Binding Proteins