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Human Molecular Genetics Advance Access originally published online on August 13, 2009
Human Molecular Genetics 2009 18(22):4329-4339; doi:10.1093/hmg/ddp385
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

RPGRIP1 is essential for normal rod photoreceptor outer segment elaboration and morphogenesis

Jungyeon Won1, Elaine Gifford1, Richard S. Smith1, Haiqing Yi2, Paulo A. Ferreira2,3, Wanda L. Hicks1, Tiansen Li4, Jürgen K. Naggert1 and Patsy M. Nishina1,*

1 The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA, 2 Department of Ophthalmology and 3 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA and 4 Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA

* To whom correspondence should be addressed. Tel: +1 2072886383; Fax: +1 2072886077; Email: patsy.nishina{at}jax.org

Received May 20, 2009; Revised July 8, 2009; Accepted August 10, 2009

The function of the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene is currently not known. However, mutations within the gene lead to Leber Congenital Amaurosis and autosomal recessive retinitis pigmentosa in human patients. In a previously described knockout mouse model of the long splice variant of Rpgrip1, herein referred to as Rpgrip1tm1Tili mice, mislocalization of key outer segment proteins and dysmorphogenesis of outer segment discs preceded subsequent photoreceptor degeneration. In this report, we describe a new mouse model carrying a splice acceptor site mutation in Rpgrip1, herein referred to as Rpgrip1nmf247 that is phenotypically distinct from Rpgrip1tm1Tili mice. Photoreceptor degeneration in homozygous Rpgrip1nmf247 mice is earlier in onset and more severe when compared with Rpgrip1tm1Tili mice. Also, ultrastructural studies reveal that whereas Rpgrip1nmf247 mutants have a normal structure and number of connecting cilia, unlike Rpgrip1tm1Tili mice, they do not elaborate rod outer segments (OS). Therefore, in addition to its role in OS disc morphogenesis, RPGRIP1 is essential for rod OS formation. Our study indicates the absence of multiple Rpgrip1 isoforms in Rpgrip1nmf247 mice, suggesting different isoforms may play different roles in photoreceptors and underscores the importance of considering splice variants when generating targeted null mutations.


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