A New Codon 15 Rhodopsin Gene Mutation in Autosomal Dominant Retinitis Pigmentosa Is Associated With Sectorial Disease

Sullivan, Laurence; Makris, George S.; Dickinson, Pamela; Mulhall, Lin; Forrest, Susan M.; Cotton, Richard G.H.; Loughnan, Michael

doi:10.1001/archopht.1993.01090110078029

Cited by 88 publications

(26 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…None of the remaining unrelated 42 ADRP, 24 autosomal recessive RP (ARRP) and 34 normal individuals had this alteration. Her funduscopic findings were sectorial in type similar to that of the patients with the same mutation found in an Australian pedigree (Sullivan et al, 1993). This study shows phenotypic similarities in patients with the same mutation of a different ancestry.…”

Section: Discussionsupporting

confidence: 76%

“…Although there is no report of Asn-15-Ser mutation of the rhodopsin gene in the USA and the UK, this particular gene mutation in an Australian pedigree was found and shown to be associated with clinical features of a sectorial phenotype observed in four generations of a family which had been positively diagnosed as having RP with impairment of the inferior half of the fundus in all affected members and with no or only mild pigmentary changes occurring along the vascular arcades (Kranich et al, 1993;Sullivan et al, 1993).…”

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

Missense mutation of rhodopsin gene codon 15 found in Japanese autosomal dominant retinitis pigmentosa

et al. 1995

View full text Add to dashboard Cite

SummaryHeterozygous missense mutation in codon 15 of the rhodopsin gene was detected in a patient with autosomal dominant retinitis pigmentosa (ADRP), where a transition of adenine to guanine at the second nucleotide in codon 15 (AAT~AGT), corresponding to a substitution of serine residue for asparagine residue (Asn-15-Ser) was detected. None of the remaining unrelated 42 ADRP, 24 autosomal recessive RP (ARRP) and 34 normal individuals had this alteration. Her funduscopic findings were sectorial in type similar to that of the patients with the same mutation found in an Australian pedigree (Sullivan et al., 1993). This study shows phenotypic similarities in patients with the same mutation of a different ancestry.

show abstract

Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 96%

Missense mutation of rhodopsin gene codon 15 found in Japanese autosomal dominant retinitis pigmentosa

et al. 1995

View full text Add to dashboard Cite

show abstract

“…PAR1 is extensively glycosylated but the nature and diversity of N-glycan modification have not been determined. Importantly, naturally occurring mutations in N-linked glycosylation consensus sequences of Rhodopsin have been linked to retinitis pigmentosa (40,41), indicating that modulation of GPCR glycosylation status can contribute to disease progression. However, mutations in PAR1 N-linked glycosylation sites have not been identified.…”

Section: Discussionmentioning

confidence: 99%

N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias

Soto

Smith

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Protease-activated receptor-1 (PAR1) is a G-protein-coupled receptor (GPCR) for the coagulant protease thrombin. Similar to other GPCRs, PAR1 is promiscuous and couples to multiple heterotrimeric G-protein subtypes in the same cell and promotes diverse cellular responses. The molecular mechanism by which activation of a given GPCR with the same ligand permits coupling to multiple G-protein subtypes is unclear. Here, we report that N-linked glycosylation of PAR1 at extracellular loop 2 (ECL2) controls G12/13 versus Gq coupling specificity in response to thrombin stimulation. A PAR1 mutant deficient in glycosylation at ECL2 was more effective at stimulating Gq-mediated phosphoinositide signaling compared with glycosylated wildtype receptor. In contrast, wildtype PAR1 displayed a greater efficacy at G12/13-dependent RhoA activation compared with mutant receptor lacking glycosylation at ECL2. Endogenous PAR1 rendered deficient in glycosylation using tunicamycin, a glycoprotein synthesis inhibitor, also exhibited increased PI signaling and diminished RhoA activation opposite to native receptor. Remarkably, PAR1 wildtype and glycosylation-deficient mutant were equally effective at coupling to Gi and β-arrestin-1. Consistent with preferential G12/13 coupling, thrombin-stimulated PAR1 wildtype strongly induced RhoA-mediated stress fiber formation compared with mutant receptor. In striking contrast, glycosylation-deficient PAR1 was more effective at increasing cellular proliferation, associated with Gq signaling, than wildtype receptor. These studies suggest that N-linked glycosylation at ECL2 contributes to the stabilization of an active PAR1 state that preferentially couples to G12/13 versus Gq and defines a previously unidentified function for N-linked glycosylation of GPCRs in regulating G-protein signaling bias.

show abstract

“…The N terminus of mature rhodopsin is dually glycosylated at residues N2 and N15 (Hargrave, 1977). Mutations of these residues or their surrounding glycosylation consensus sequences (T4K, N15S, and T17M) are linked to a subset of RP known as sector RP in which the inferior retina is primarily affected, potentially attributable to greater light exposure to this region (Fishman et al, 1992;Sullivan et al, 1993;Li et al, 1994;van den Born et al, 1994). Furthermore, both transgenic mice expressing human T17M rhodopsin (White et al, 2007) and a naturally occurring dog model harboring a rhodopsin T4R mutation exhibit lightsensitive retinal degeneration (Kijas et al, 2002;Cideciyan et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The Role of Rhodopsin Glycosylation in Protein Folding, Trafficking, and Light-Sensitive Retinal Degeneration

Tam¹,

Moritz²

2009

J. Neurosci.

View full text Add to dashboard Cite

Several mutations in the N terminus of the G-protein-coupled receptor rhodopsin disrupt NXS/T consensus sequences for N-linked glycosylation (located at N2 and N15) and cause sector retinitis pigmentosa in which the inferior retina preferentially degenerates. Here we examined the role of rhodopsin glycosylation in biosynthesis, trafficking, and retinal degeneration (RD) using transgenic Xenopus laevis expressing glycosylation-defective human rhodopsin mutants. Although mutations T4K and T4N caused RD, N2S and T4V did not, demonstrating that glycosylation at N2 was not required for photoreceptor viability. In contrast, similar mutations eliminating glycosylation at N15 (N15S and T17M) caused rod death. Expression of T17M was more toxic than T4K to transgenic photoreceptors, further suggesting that glycosylation at N15 plays a more important physiological role than glycosylation at N2. Together, these results indicate that the structure of the rhodopsin N terminus must be maintained by an appropriate amino acid sequence surrounding N2 and may require a carbohydrate moiety at N15. The mutant rhodopsins were rendered less toxic in their dark inactive states, because RD was abolished or significantly reduced when transgenic tadpoles expressing T4K, T17M, and N2S/N15S were protected from light exposure. Regardless of their effect on rod viability, all of the mutants primarily localized to the outer segment and Golgi and showed little or no endoplasmic reticulum accumulation. Thus, glycosylation was not crucial for rhodopsin biosynthesis or trafficking. Interestingly, expression of similar bovine rhodopsin mutants did not cause rod cell death, possibly attributable to greater stability of bovine rhodopsin.

show abstract

A New Codon 15 Rhodopsin Gene Mutation in Autosomal Dominant Retinitis Pigmentosa Is Associated With Sectorial Disease

Cited by 88 publications

References 22 publications

Missense mutation of rhodopsin gene codon 15 found in Japanese autosomal dominant retinitis pigmentosa

Missense mutation of rhodopsin gene codon 15 found in Japanese autosomal dominant retinitis pigmentosa

N-linked glycosylation of protease-activated receptor-1 at extracellular loop 2 regulates G-protein signaling bias

The Role of Rhodopsin Glycosylation in Protein Folding, Trafficking, and Light-Sensitive Retinal Degeneration

Contact Info

Product

Resources

About