A single amino acid substitution (Cys249Trp) in the sixth epidermal growth factor (EGF) domain of Crb1 causes retinal degeneration and deregulates expression of Pituitary tumor transforming gene 1 (Pttg1)

TY - JOUR

T1 - A single amino acid substitution (Cys249Trp) in the sixth epidermal growth factor (EGF) domain of Crb1 causes retinal degeneration and deregulates expression of Pituitary tumor transforming gene 1 (Pttg1)

AU - van de Pavert, SA

AU - Meuleman, J

AU - Malysheva, A

AU - Aartsen, WM

AU - Versteeg, I

AU - Kamphuis, W

AU - McCabe, Christopher

AU - Seeliger, M

AU - Wijnholds, J

PY - 2007/1/17

Y1 - 2007/1/17

N2 - Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e. g., RP12), RP with Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Muller glia cells. To gain insight into genotype - phenotype relationship, we generated Crb1(C249W) mice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1C249W as wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients. Crb1C249W mice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts in Crb1(C249W/-) knock-in and Crb1(-/-) knock-out compared with control retinas. Exposure to white light decreased levels of Pttg1 in Crb1 mutant retinas. We hypothesize deregulation of Pttg1 expression attributable to a C249W substitution in the extracellular domain of Crb1.

AB - Different mutations in the human Crumbs homolog-1 (CRB1) gene cause a variety of retinal dystrophies, such as Leber congenital amaurosis, early onset retinitis pigmentosa (e. g., RP12), RP with Coats-like exudative vasculopathy, and pigmented paravenous retinochoroidal atrophy. Loss of Crb1 leads to displaced photoreceptors and focal degeneration of all neural layers attributable to loss of adhesion between photoreceptors and Muller glia cells. To gain insight into genotype - phenotype relationship, we generated Crb1(C249W) mice that harbor an amino acid substitution (Cys249Trp) in the extracellular sixth calcium-binding epidermal growth factor domain of Crb1. Our analysis showed that Crb1C249W as wild-type protein trafficked to the subapical region adjacent to adherens junctions at the outer limiting membrane (OLM). Hence, these data suggest correct trafficking of the corresponding mutant CRB1 in RP12 patients. Crb1C249W mice showed loss of photoreceptors in the retina, relatively late compared with mice lacking Crb1. Scanning laser ophthalmoscopy revealed autofluorescent dots that presumably represent layer abnormalities after OLM disturbance. Gene expression analyses revealed lower levels of pituitary tumor transforming gene 1 (Pttg1) transcripts in Crb1(C249W/-) knock-in and Crb1(-/-) knock-out compared with control retinas. Exposure to white light decreased levels of Pttg1 in Crb1 mutant retinas. We hypothesize deregulation of Pttg1 expression attributable to a C249W substitution in the extracellular domain of Crb1.

KW - knock-out mice

KW - photoreceptors

KW - retinal degeneration

KW - retinitis pigmentosa (RP)

KW - blindness

KW - Muller glia cells

KW - adhesion

KW - Leber congenital amaurosis (LCA)

KW - mutant

KW - retina

UR - http://www.scopus.com/inward/record.url?scp=33846420195&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3496-06.2007

DO - 10.1523/JNEUROSCI.3496-06.2007

M3 - Article

VL - 273

SP - 564

EP - 573

JO - The Journal of Neuroscience

JF - The Journal of Neuroscience

SN - 0270-6474

ER -