Mutation screen of the cone-specific gene, CLUL1, in 376 patients with age-related macular degeneration.

Clusterin is a secreted glycoprotein expressed ubiquitously in many tissues that appears to function as a molecular chaperone capable of protecting stressed proteins. It is upregulated in many different forms of neurodegeneration and is thought to represent a defense response against neuronal damage. Clusterin has been found to be a common protein identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. A retina-specific clusterin-like protein (CLUL1) showing nearly 25% identity to clusterin at the protein level was recently cloned and shown to be expressed specifically in cone photoreceptor cells. For these reasons, we investigated CLUL1 as a candidate gene for AMD. A mutation screen of the entire coding region of the CLUL1 gene in 376 unrelated patients with AMD uncovered three sequence variations, one isocoding change and two intronic changes. One intronic change appears significantly less frequent in patients with the more severe forms of AMD than in control subjects, suggesting that this variant may reduce the risk for AMD or may be linked to a nearby variant that may reduce AMD risk. Variant alleles of the CLUL1 gene were found; however, none are considered pathogenic. None of the variants identified are predicted to create or destroy splice donor or acceptor sites based on splice-site prediction software.

Visual and vestibular determinants of the translational vestibulo-ocular reflex.

Prior studies indicate that the human translational vestibulo-ocular reflex (tVOR) generates eye rotations approximately half the magnitude required to keep the line of sight pointed at a stationary object--a compensation ratio (CR) of ∼0.5. We asked whether changes of visual or vestibular stimuli could increase the CR of tVOR. First, subjects viewed their environment through an optical device that required eye movements to increase by ∼50% to maintain fixation of a stationary visual target. During vertical translation, eye movements did increase, but tVOR CR remained at ∼0.5. Second, subjects viewed through LCD goggles providing 4 Hz strobe vision that minimized retinal image motion; this reduced tVOR CR. Finally, subjects were rotated in roll while they translated vertically; no increase in tVOR occurred. Taken with prior studies, we conclude that tVOR is optimally set to generate eye rotations that are about 50% of those required to stabilize the line of sight.

Mutation screen of beta-crystallin genes in 274 patients with age-related macular degeneration.

PURPOSE: The crystallin family of proteins comprise the main structural proteins of the vertebrate lens and have been classified into alpha-, beta-, and gamma- families. Several of the beta-crystallin proteins have been detected in the retina where they are each localized to different compartments of rod and cone photoreceptors. Functionally, beta-crystallins have been implicated in the protection of the retina from intense light exposure. Two members of the beta-crystallins, CRYBB1 and CRYBB2, have been identified in drusen preparations isolated from the retina of donor eyes of patients with age-related macular degeneration (AMD), the leading cause of blindness in the elderly population of developed countries. We therefore investigated CRYBB1 and CRYBB2 as candidate genes for AMD in 274 unrelated patients. RESULTS: A mutation screen of the entire coding region of the CRYBB1gene uncovered eight sequence variations, including three missense changes, two intronic changes and three isocoding changes. A mutation screen of the entire coding region of the CRYBB2 gene uncovered three sequence variations, one isocoding change and two intronic changes. CONCLUSIONS: Although variant alleles of the CRYBB1 and CRYBB2 genes were found, none are considered pathogenic.