PUBLICATION
Human retinopathy-associated ciliary protein Retinitis Pigmentosa GTPase Regulator (RPGR) regulates cilia-dependent vertebrate development
- Authors
- Ghosh, A.K., Murga-Zamalloa, C.A., Chan, L., Hitchcock, P.F., Swaroop, A., and Khanna, H.
- ID
- ZDB-PUB-091023-28
- Date
- 2010
- Source
- Human molecular genetics 19(1): 90-98 (Journal)
- Registered Authors
- Khanna, Hemant
- Keywords
- none
- MeSH Terms
-
- Animals
- Cilia/drug effects
- Cilia/metabolism*
- Cilia/pathology
- Embryo, Nonmammalian/abnormalities
- Embryo, Nonmammalian/metabolism
- Eye Proteins/genetics
- Eye Proteins/metabolism*
- Gene Expression Regulation, Developmental/drug effects
- Gene Knockdown Techniques
- Humans
- Mutant Proteins/metabolism
- Mutation/genetics
- Oligonucleotides, Antisense/pharmacology
- Phenotype
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 19815619 Full text @ Hum. Mol. Genet.
Citation
Ghosh, A.K., Murga-Zamalloa, C.A., Chan, L., Hitchcock, P.F., Swaroop, A., and Khanna, H. (2010) Human retinopathy-associated ciliary protein Retinitis Pigmentosa GTPase Regulator (RPGR) regulates cilia-dependent vertebrate development. Human molecular genetics. 19(1):90-98.
Abstract
Dysfunction of primary cilia is associated with tissue-specific or syndromic disorders. RPGR is a ciliary protein, mutations in which can lead to retinitis pigmentosa (RP), cone-rod degeneration, respiratory infections, and hearing disorders. Though RPGR is implicated in ciliary transport, the pathogenicity of RPGR mutations and the mechanism of underlying phenotypic heterogeneity are still unclear. Here we have utilized genetic rescue studies in zebrafish to elucidate the effect of human disease-associated mutations on its function. We show that rpgr is expressed predominantly in the retina, brain, and gut of zebrafish. In the retina, RPGR primarily localizes to the sensory cilium of photoreceptors. Antisense morpholino (MO)-mediated knockdown of rpgr function in zebrafish results in reduced length of Kupffer's vesicle (KV) cilia and is associated with ciliary anomalies including shortened body-axis, kinked tail, hydrocephaly, and edema but does not affect retinal development. These phenotypes can be rescued by wild type (WT) human RPGR. Several of the RPGR mutants can also reverse the MO-induced phenotype, suggesting their potential hypomorphic function. Notably, selected RPGR mutations observed in XLRP (T99N, E589X) or syndromic RP (T124fs, K190fs, and L280fs) do not completely rescue the rpgr-MO phenotype, indicating a more deleterious effect of the mutation on the function of RPGR. We propose that RPGR is involved in cilia-dependent cascades during development in zebrafish. Our studies provide evidence for a heterogenic effect of the disease-causing mutations on the function of RPGR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping