Macular Degeneration: Lachapelle P

Houssier M, Raoul W, Lavalette S, Keller N, Guillonneau X, Baragatti B, Jonet L, Jeanny JC, Behar-Cohen F, Coceani F, Scherman D, Lachapelle P, Ong H, Chemtob S, Sennlaub F. · Institut National de la Santé et de la Recherche Médicale U872, Paris, France. · PLoS Med. · Pubmed #18288886 links to  free full text

Abstract: BACKGROUND: In the Western world, a major cause of blindness is age-related macular degeneration (AMD). Recent research in angiogenesis has furthered the understanding of choroidal neovascularization, which occurs in the "wet" form of AMD. In contrast, very little is known about the mechanisms of the predominant, "dry" form of AMD, which is characterized by retinal atrophy and choroidal involution. The aim of this study is to elucidate the possible implication of the scavenger receptor CD36 in retinal degeneration and choroidal involution, the cardinal features of the dry form of AMD. METHODS AND FINDINGS: We here show that deficiency of CD36, which participates in outer segment (OS) phagocytosis by the retinal pigment epithelium (RPE) in vitro, leads to significant progressive age-related photoreceptor degeneration evaluated histologically at different ages in two rodent models of CD36 invalidation in vivo (Spontaneous hypertensive rats (SHR) and CD36-/- mice). Furthermore, these animals developed significant age related choroidal involution reflected in a 100%-300% increase in the avascular area of the choriocapillaries measured on vascular corrosion casts of aged animals. We also show that proangiogenic COX2 expression in RPE is stimulated by CD36 activating antibody and that CD36-deficient RPE cells from SHR rats fail to induce COX2 and subsequent vascular endothelial growth factor (VEGF) expression upon OS or antibody stimulation in vitro. CD36-/- mice express reduced levels of COX2 and VEGF in vivo, and COX2-/- mice develop progressive choroidal degeneration similar to what is seen in CD36 deficiency. CONCLUSIONS: CD36 deficiency leads to choroidal involution via COX2 down-regulation in the RPE. These results show a novel molecular mechanism of choroidal degeneration, a key feature of dry AMD. These findings unveil a pathogenic process, to our knowledge previously undescribed, with important implications for the development of new therapies.

Yzer S, Fishman GA, Racine J, Al-Zuhaibi S, Chakor H, Dorfman A, Szlyk J, Lachapelle P, van den Born LI, Allikmets R, Lopez I, Cremers FP, Koenekoop RK. · McGill Ocular Genetics Centre, Division of Ophthalmology, Montreal, Quebec, Canada. · Invest Ophthalmol Vis Sci. · Pubmed #16936081 links to  free full text

Abstract: PURPOSE: To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS: Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS: Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS: In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.