Mouse Choroideremia Gene Mutation Causes Photoreceptor Cell Degeneration and is not Transmitted through the Female Germline

• Published in: Human molecular genetics Vol. 6; no. 6; pp. 851 - 858
• Main Authors: van den Hurk, José A. J. M., Hendriks, Wiljan, van de Pol, Dorien J. R., Oerlemans, Frank, Jaissle, Gesine, Ruther, Klaus, Kohler, Konrad, Hartmann, Jens, Zrenner, Eberhart, van Bokhoven, Hans, Wieringa, Bé, Ropers, Hans-Hilger, Cremers, Frans P. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.06.1997
• Subjects: Alkyl and Aryl Transferases; Animals; Biological and medical sciences; Blastomeres; Carrier Proteins - genetics; Choroideremia - genetics; Choroideremia - pathology; Disease Models, Animal; Female; Gene Targeting; Germ Cells; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mutation; Ophthalmology; Photoreceptor Cells - pathology; Polymerase Chain Reaction; rab GTP-Binding Proteins; Retinopathies; Sex linked character; Animal model; Genetic inheritance; Maternal origin; Rodentia; Photoreceptor; Retina; Uvea disease; Lethal character; Genetic disease; Eye disease; Vertebrata; Phenotype; Mammalia; Gene; Mouse; Choroideremia; Genetics; Degeneration; Mutation
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/6.6.851

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.