Abstract
Peripherin/rds is an integral membrane glycoprotein found in the rim regions of vertebrate photoreceptor cell discs. Natural mutations of the encoding gene result in degenerative retinal disorders, such as retinitis pigmentosa. The retinal degeneration slow (rds) phenotype, observed in mice, is considered to be an appropriate model for peripherin/rds-mediated retinitis pigmentosa. Associated abnormalities in the outer segment of photoreceptor cells have implicated peripherin/rds in some aspect of disc morphology, yet it remains unclear whether such morphological effects are the cause or the result of this condition. Here we present the first direct evidence to support a role for peripherin/rds in maintaining the flattened vesicle morphology characteristic of photoreceptor outer segments. In vitro expression yields a 36-kDa immunoreactive species, which is inserted into membranes and undergoes N-glycosylation, inter- and intramolecular disulfide bonding, and dimerization. Electron microscopy reveals that peripherin/rds flattens microsomal vesicles. This effect appears to be dependent on disulfide bond formation but not N-glycosylation. The inability of two pathogenic peripherin/rds mutants (P216L and C165Y) to flatten membrane vesicles implicates such mutations as the primary cause of the retinal degeneration observed in retinitis pigmentosa.
Highlights
From the School of Biochemistry and Molecular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom
This evidence has led to the proposition that peripherin/rds plays a role in maintenance of the curvature of the rim region and the flattened vesicle morphology [3, 4, 12]
The mapping of the rds phenotype to a genetic lesion in the cloned gene has led to the proposal that peripherin/rds plays a crucial role in the maintenance of photoreceptor disc morphology
Summary
Received for publication, October 18, 1999, and in revised form, February 28, 2000. Jonathan D. The outer segment of the vertebrate rod photoreceptor cell exhibits a highly specialized structure, comprised of a stack of 1000 or more flattened vesicles or discs [1]. Heterozygous mice possess reduced levels of peripherin/rds and form highly abnormal outer segments, which are much shorter in length, with the disc membranes aligned in irregular whorls that appear swollen and vacuolated [11]. This evidence has led to the proposition that peripherin/rds plays a role in maintenance of the curvature of the rim region and the flattened vesicle morphology [3, 4, 12]. Site-directed mutagenesis was used to demonstrate that pathogenic mutants of peripherin/rds are unable to elicit this effect
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