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

Jung, Won Seok; Gifford, Elaine J; Smith, Richard; Yi, Haiqing; Ferreira, Paulo A.; Hicks, Wanda L.; Li, Tiansen; Naggert, Jürgen Κ.; Nishina, Patsy M.

doi:10.1093/hmg/ddp385

Cited by 61 publications

(104 citation statements)

References 47 publications

(49 reference statements)

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“…A second mouse model carrying a recessive RPGRIP1 mutation, designated Rpgrip1 nmf247 , was identified in an ethyl nitrosourea (ENU) chemical mutagenesis screen at the Jackson laboratory (Won et al 2009). The mutation alters a splice site at exon 7 and results in skipping of exons 7 and 8 in the mRNA and premature termination of the open reading frame.…”

Section: Animal Modelsmentioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

2014

Cold Spring Harbor Perspectives in Medicine

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Recessive null mutations in retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene are the cause of LCA6 and account for 5% to 6% of the total patient population. RPGRIP1 has an essential role in the photoreceptor connecting cilia, and photoreceptors lacking RPGRIP1 are unable to maintain the light sensing outer segments. As a result, patients lose retinal functions at an early age but retain photoreceptors in the central retina well into adulthood thus holding out the prospect for gene augmentation therapies. Laboratory studies in animal models have demonstrated efficacy of gene therapy in slowing disease progression. With further refinement in the design of the replacement gene construct, clinical trials for Leber congenital amaurosis (LCA) caused by RPGRIP1 mutations could be in the offing in the near future.

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Section: Animal Modelsmentioning

confidence: 99%

Leber Congenital Amaurosis Caused by Mutations in RPGRIP1

2014

Cold Spring Harbor Perspectives in Medicine

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“…Primer sequences are shown in Supplemental Table 5. Genomic DNA was isolated from tail tip, and PCR amplicons were obtained and visualized as previously described (12). Procedures using mice were approved by The Jackson Laboratory Institutional Animal Care and Use Committee.…”

Section: Generation Of Gene Trap Animals and Husbandry Es Cells Contmentioning

confidence: 99%

“…12) and CEP290 (rd16; ref. 13) display mislocalization of phototransducing proteins in combination with photoreceptor function loss and rapid photoreceptor degeneration.…”

Section: Introductionmentioning

confidence: 99%

Disruption of intraflagellar protein transport in photoreceptor cilia causes Leber congenital amaurosis in humans and mice

Boldt¹,

Mans²,

Jung³

et al. 2011

J. Clin. Invest.

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114

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The mutations that cause Leber congenital amaurosis (LCA) lead to photoreceptor cell death at an early age, causing childhood blindness. To unravel the molecular basis of LCA, we analyzed how mutations in LCA5 affect the connectivity of the encoded protein lebercilin at the interactome level. In photoreceptors, lebercilin is uniquely localized at the cilium that bridges the inner and outer segments. Using a generally applicable affinity proteomics approach, we showed that lebercilin specifically interacted with the intraflagellar transport (IFT) machinery in HEK293T cells. This interaction disappeared when 2 human LCA-associated lebercilin mutations were introduced, implicating a specific disruption of IFT-dependent protein transport, an evolutionarily conserved basic mechanism found in all cilia. Lca5 inactivation in mice led to partial displacement of opsins and light-induced translocation of arrestin from photoreceptor outer segments. This was consistent with a defect in IFT at the connecting cilium, leading to failure of proper outer segment formation and subsequent photoreceptor degeneration. These data suggest that lebercilin functions as an integral element of selective protein transport through photoreceptor cilia and provide a molecular demonstration that disrupted IFT can lead to LCA.

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“…195 Loss of RPGRIP1 has no effect on central (cone-rich) retinal architecture 196 but it is required for rod OS structure 197 and mice lacking RPGRIP1 develop grossly oversized OS discs.…”

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confidence: 99%