Abnormal Axonemes in X-linked Retinitis Pigmentosa

Hunter, David G.; Fishman, Gerald A.; Kretzer, Frank L.

doi:10.1001/archopht.1988.01060130388028

Cited by 46 publications

(26 citation statements)

References 40 publications

(2 reference statements)

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“…Abnormal sperm tails and instability of sperm axonemes have been observed in patients with XLRP (33). RPGR-ORF15 staining in the tip and the axoneme of mouse sperm flagella is consistent with these clinical findings.…”

Section: Discussioncontrasting

confidence: 40%

RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins

Khanna

Hurd

Lillo

et al. 2005

Journal of Biological Chemistry

154

176

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Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene account for almost 20% of patients with retinitis pigmentosa. Most mutations are detected in alternatively spliced RPGR-ORF15 isoform(s), which are primarily but not exclusively expressed in the retina. We show that, in addition to the axoneme, the RPGR-ORF15 protein is localized to the basal bodies of photoreceptor connecting cilium and to the tip and axoneme of sperm flagella. Mass spectrometric analysis of proteins that were immunoprecipitated from the retinal axoneme-enriched fraction using an anti-ORF15 antibody identified two chromosome-associated proteins, structural maintenance of chromosomes (SMC) 1 and SMC3. Using pulldown assays, we demonstrate that the interaction of RPGR with SMC1 and SMC3 is mediated, at least in part, by the RCC1-like domain of RPGR. This interaction was not observed with phosphorylation-deficient mutants of SMC1. Both SMC1 and SMC3 localized to the cilia of retinal photoreceptors and Madin-Darby canine kidney cells, suggesting a broader physiological relevance of this interaction. Additional immunoprecipitation studies revealed the association of RPGR-ORF15 isoform(s) with the intraflagellar transport polypeptide IFT88 as well as microtubule motor proteins, including KIF3A, p150Glued , and p50-dynamitin. Inhibition of dynein function by overexpressing p50 abrogated the localization of RPGR-ORF15 to basal bodies. Taken together, these results provide novel evidence for the possible involvement of RPGR-ORF15 in microtubule organization and regulation of transport in primary cilia. X-linked retinitis pigmentosa (XLRP)4 (MIM 312610) is a relatively severe and genetically heterogeneous inherited retinal degeneration.RP3 is the major subtype of XLRP accounting for over 70% of affected families (1, 2). The RP3 gene, called retinitis pigmentosa GTPase regulator (RPGR), encodes several distinct alternatively spliced transcripts that are widely expressed (3-5). Mutations in the constitutive RPGR protein of 815 amino acids are detected in ϳ20% of XLRP (6). Subsequent studies revealed an unusual exon, ORF15 (immediately following exon 15) encoding a Gly-and Glu-rich carboxyl-terminal domain of 567 amino acids; mutations in ORF15 accounted for an additional 50% of XLRP patients and 25% of RP males with no family history (7-9). Several distinct RPGR isoforms that include complete or part of ORF15 (RPGR-ORF15) are detected preferentially, but not exclusively, in the retina (7, 10) and localized to the connecting cilium and/or outer segments of photoreceptors (11-13).The amino-terminal region of RPGR (termed RCC1-like domain, RLD) shows homology to RCC1, a guanine nucleotide exchange factor for Ran, a GTPase involved in nucleocytoplasmic transport (14). Hence, RPGR was predicted to be a guanine nucleotide exchange factor for a small GTP-binding protein. However, no such activity or interaction has yet been demonstrated. Yeast two-hybrid analysis using RPGR-RLD had previously identified two proteins, RPGRIP1 (RPGR-interacting prot...

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Section: Discussioncontrasting

confidence: 40%

RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins

Khanna

Hurd

Lillo

et al. 2005

Journal of Biological Chemistry

154

176

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“…Abnormalities in cilia have been reported in X-linked and autosomal types of RP [Arden and Fox, 1979;Fox et al, 1980;Hunter et al, 1988]. The localization of RPGR to the rod and cone photoreceptor connecting cilium [Hong et al, 2000] raises the possibility that the observed ciliary abnormalities in XLRP are associated with RPGR mutations.…”

Section: Ciliary Abnormalities In Xlrpsupporting

confidence: 39%

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Vervoort

Wright

2002

Hum. Mutat.

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Mutations in RPGR, retinitis pigmentosa GTPase regulator, are associated with RP3 type of Xlinked retinitis pigmentosa, a severe, non-syndromic form of retinal degeneration. In the majority of subjects RPGR mutations are associated with a typical rod-cone degeneration, but in a small number, cone-rod dystrophy, deafness, and abnormalities in respiratory cilia have been noted. Alternative splicing of RPGR is complex in all species examined. In RP3 patients, mutations have been found in exons 1 14 and ORF15, thus delineating a transcript necessary for normal retinal function in humans. The great majority of mutations are predicted to result in premature termination of translation. These mutations are scattered over exons 1 14 and ORF15, while most missense mutations occur in a domain with homology to the protein RCC1, encoded by exons 1 10. Exon ORF15 is a hot spot for mutation, at least in the British population, in which it harbors 80% of the mutations found within a sample of 47 X-linked retinitis pigmentosa patients. Most RPGR mutations are unique to single families, which makes it difficult to demonstrate phenotype genotype correlations. Hum Mutat 19:486 500, 2002.

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“…Such selective bias or meiotic drive has not been reported previously with any of the other RDS-associated alleles, although patients with X-linked retinitis pigmentosa and Usher syndrome have been known to manifest alterations in sperm morphology without known alterations in fertility. 42,43 The variability of clinical phenotype among individuals carrying the Tyr141Cys mutation in the SUNY901 pedigree suggests potential involvement of other modifier genes or the possible contribution of environmental and other stochastic factors to the pathogenesis of the maculopathy. We investigated this possibility in our group by mutation analysis of the unlinked ROM1 gene.…”

Section: Discussionmentioning

confidence: 42%

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

Khani

Karoukis

Young

et al. 2003

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To examine the molecular genetic basis and phenotypic characteristics of an unusual late-onset autosomal dominant macular dystrophy with features of age-related macular degeneration (AMD) in a large family (SUNY901), by using linkage and mutation analyses. METHODS. Blood samples were collected from 17 affected members, 17 clinically unaffected members, and 5 unrelated spouses. Clinical analyses included a review of medical history and standard ophthalmic examination with fundus photography, fluorescein angiography, and electroretinography. Linkage and haplotype analyses were performed with microsatellite markers. Mutation analysis was performed by amplification of exons followed by sequencing. RESULTS. A wide spectrum of clinical phenotypes including exudative and nonexudative maculopathy was observed, with onset in the late fifth decade. Linkage analysis excluded most of the previously known maculopathy loci. Markers D6S1604 (Z max of 3.18 at ϭ 0), and D6S282 (Z max of 3.18 at ϭ 0) gave significant positive LOD scores and haplotype analysis localized the disease gene to a 9-centimorgan (cM) interval between markers D6S1616 and D6S459. Mutation analysis excluded the GUCA1A and GUCA1B genes and revealed a missense mutation in the RDS/peripherin gene leading to a Tyr141Cys substitution. A phenotype and haplotype comparison between this and a separate family with the Tyr141Cys mutation suggested the presence of a common ancestral haplotype. CONCLUSIONS.The RDS mutation in codon 141 is associated with an unusual AMD-like late-onset maculopathy. An apparent selective bias was noted favoring the transmission of the mutant allele. These observations broaden the spectrum of phenotypes associated with RDS gene mutations. (Invest Ophthalmol Vis Sci.

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Abnormal Axonemes in X-linked Retinitis Pigmentosa

Cited by 46 publications

References 40 publications

RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins

RPGR-ORF15, Which Is Mutated in Retinitis Pigmentosa, Associates with SMC1, SMC3, and Microtubule Transport Proteins

Mutations ofRPGR in X-linked retinitis pigmentosa (RP3)

Late-Onset Autosomal Dominant Macular Dystrophy with Choroidal Neovascularization and Nonexudative Maculopathy Associated with Mutation in theRDSGene

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