An unusual retinal vascular morphology in connection with a novel AIPL1 mutation in Leber's congenital amaurosis

Abstract

Aims: To report a case of an unusual retinal vascular morphology in connection with a novel AIPL1 mutation in a patient with Leber's congenital amaurosis (LCA). Methods: A patient with LCA and no light perception from birth had both eyes enucleated at the age of 22 years because of excruciating pain. Mutation analysis was performed on known LCA genes. The eyes were processed for casts of the vascular tree, routine histopathology, and electron microscopy. Results: A novel H82Y (244C→T) mutation and a H90D (286G→C) polymorphism were detected in exon 2 of the AIPL1 gene. Both the cast and the histopathological examination showed dilated retinal vessels, mainly venules, primarily localised in the posterior pole. In the mid-peripheral retina the density of capillaries on the arteriolar side of the microcirculatory units was significantly decreased. The vascular system was seen to gradually attenuate towards the retinal periphery, and to stop at a zone located approximately 4 mm from the ora serrata along the whole circumference. In this zone pigmented aggregates characteristic of retinitis pigmentosa were seen to ensheath the retinal vessels. The photoreceptors were almost totally absent and retinal gliosis was present. A decreased number of ganglion cells and an increased vacuolisation of the nerve fibre layer were observed. The retinal pigment cells and Bruch's membrane appeared normal in all regions. Conclusion: An unusual retinal vascular morphology in an LCA patient is presented and possible pathogenic mechanisms of the findings are discussed.

Microscopic Inner Retinal Hyper-Reflective Phenotypes in Retinal and Neurologic Disease

“…In contrast to the membranes described earlier, these vessel coatings reside just posterior to the NFL as shown by OCT B-scans. In Leber's congenital amaurosis, it has been shown that some genotypes have inflammatory and glial proliferations surrounding the vessels, 45 consistent with the findings in Figure 12.…”

Microscopic Inner Retinal Hyper-Reflective Phenotypes in Retinal and Neurologic Disease

“…In contrast to the membranes described earlier, these vessel coatings reside just posterior to the NFL as shown by OCT B-scans. In Leber's congenital amaurosis, it has been shown that some genotypes have inflammatory and glial proliferations surrounding the vessels, 45 consistent with the findings in Figure 12.…”

The Leber Congenital Amaurosis Protein AIPL1 Functions as Part of a Chaperone Heterocomplex

“…2). Sequence changes that have been associated with LCA pathogenesis were tested (H82Y, A197P, C239R, G262S, W278X, R302L) 1,34,35. G262S and R302L were able to interact with both molecular chaperones, similar to the wild-type protein, whereas H82Y appeared to have very slightly reduced growth with Hsp70.…”

“…The H82Y and R302L amino acid changes are controversial in their disease-causing status 35,43. The AIPL1 H82Y mutation was first described as a heterozygous change in an LCA patient,34 and R302L may not be a disease-causing variant of AIPL1 but rather a rare benign variant given that nonconservative residues occur at this position in other species 35. Therefore, further patient/population DNA and protein analyses are needed to determine the status of these sequence changes.…”

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation

“…Next, based on oximetry biomarkers from human retinal arterioles [ 10 ], a scaling factor of 3.6 was used to convert murine vessel diameters to human values. Last, the distance from the CRA to the fovea in the human retina (approximately 4.5 mm) was used to determine a 5.9 scaling factor between mouse and human vessel lengths [ 11 , 12 ]. Importantly, the heterogeneity of the network branching structure was assumed to be similar between species since several studies have indicated that the morphology of the human and murine vascular networks is strikingly similar [ 13 , 14 ].…”

Microscopic Inner Retinal Hyper-Reflective Phenotypes in Retinal and Neurologic Disease

“…In contrast to the membranes described earlier, these vessel coatings reside just posterior to the NFL as shown by OCT B-scans. In Leber's congenital amaurosis, it has been shown that some genotypes have inflammatory and glial proliferations surrounding the vessels, 45 consistent with the findings in Figure 12.…”

The Leber Congenital Amaurosis Protein AIPL1 Functions as Part of a Chaperone Heterocomplex

“…2). Sequence changes that have been associated with LCA pathogenesis were tested (H82Y, A197P, C239R, G262S, W278X, R302L) 1,34,35. G262S and R302L were able to interact with both molecular chaperones, similar to the wild-type protein, whereas H82Y appeared to have very slightly reduced growth with Hsp70.…”

“…The H82Y and R302L amino acid changes are controversial in their disease-causing status 35,43. The AIPL1 H82Y mutation was first described as a heterozygous change in an LCA patient,34 and R302L may not be a disease-causing variant of AIPL1 but rather a rare benign variant given that nonconservative residues occur at this position in other species 35. Therefore, further patient/population DNA and protein analyses are needed to determine the status of these sequence changes.…”

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation

“…Next, based on oximetry biomarkers from human retinal arterioles [ 10 ], a scaling factor of 3.6 was used to convert murine vessel diameters to human values. Last, the distance from the CRA to the fovea in the human retina (approximately 4.5 mm) was used to determine a 5.9 scaling factor between mouse and human vessel lengths [ 11 , 12 ]. Importantly, the heterogeneity of the network branching structure was assumed to be similar between species since several studies have indicated that the morphology of the human and murine vascular networks is strikingly similar [ 13 , 14 ].…”

Microscopic Inner Retinal Hyper-Reflective Phenotypes in Retinal and Neurologic Disease

“…In contrast to the membranes described earlier, these vessel coatings reside just posterior to the NFL as shown by OCT B-scans. In Leber's congenital amaurosis, it has been shown that some genotypes have inflammatory and glial proliferations surrounding the vessels, 45 consistent with the findings in Figure 12.…”

The Leber Congenital Amaurosis Protein AIPL1 Functions as Part of a Chaperone Heterocomplex

“…2). Sequence changes that have been associated with LCA pathogenesis were tested (H82Y, A197P, C239R, G262S, W278X, R302L) 1,34,35. G262S and R302L were able to interact with both molecular chaperones, similar to the wild-type protein, whereas H82Y appeared to have very slightly reduced growth with Hsp70.…”

“…The H82Y and R302L amino acid changes are controversial in their disease-causing status 35,43. The AIPL1 H82Y mutation was first described as a heterozygous change in an LCA patient,34 and R302L may not be a disease-causing variant of AIPL1 but rather a rare benign variant given that nonconservative residues occur at this position in other species 35. Therefore, further patient/population DNA and protein analyses are needed to determine the status of these sequence changes.…”

Metabolic Signaling in a Theoretical Model of the Human Retinal Microcirculation

“…Next, based on oximetry biomarkers from human retinal arterioles [ 10 ], a scaling factor of 3.6 was used to convert murine vessel diameters to human values. Last, the distance from the CRA to the fovea in the human retina (approximately 4.5 mm) was used to determine a 5.9 scaling factor between mouse and human vessel lengths [ 11 , 12 ]. Importantly, the heterogeneity of the network branching structure was assumed to be similar between species since several studies have indicated that the morphology of the human and murine vascular networks is strikingly similar [ 13 , 14 ].…”