Disruption of murineAdamtsl4results in zonular fiber detachment from the lens and in retinal pigment epithelium dedifferentiation

Abstract

Human gene mutations have revealed that a significant number of ADAMTS (a disintegrin-like and metalloproteinase (reprolysin type) with thrombospondin type 1 motifs) proteins are necessary for normal ocular development and eye function. Mutations in human ADAMTSL4, encoding an ADAMTS-like protein which has been implicated in fibrillin microfibril biogenesis, cause ectopia lentis (EL) and EL et pupillae. Here, we report the first ADAMTSL4 mouse model, tvrm267, bearing a nonsense mutation in Adamtsl4. Homozygous Adamtsl4(tvrm267) mice recapitulate the EL phenotype observed in humans, and our analysis strongly suggests that ADAMTSL4 is required for stable anchorage of zonule fibers to the lens capsule. Unexpectedly, homozygous Adamtsl4(tvrm267) mice exhibit focal retinal pigment epithelium (RPE) defects primarily in the inferior eye. RPE dedifferentiation was indicated by reduced pigmentation, altered cellular morphology and a reduction in RPE-specific transcripts. Finally, as with a subset of patients with ADAMTSL4 mutations, increased axial length, relative to age-matched controls, was observed and was associated with the severity of the RPE phenotype. In summary, the Adamtsl4(tvrm267) model provides a valuable tool to further elucidate the molecular basis of zonule formation, the pathophysiology of EL and ADAMTSL4 function in the maintenance of the RPE.

Histologic and Optical Coherence Tomographic Correlates in Drusenoid Pigment Epithelium Detachment in Age-Related Macular Degeneration

“…Although most swarms comprised groups of cells, we did also note some large individual cells that were multinucleate 29,30 (Figure 5). Experimental studies in mouse demonstrated that multinucleate RPE cells in the setting of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif-like 4-deficiency can be migratory 37 , suggestive of a final common pathway to different stresses, while others indicate that failed cytokinesis in cell division can cause RPE multinucleation. 38 One interesting group of intraretinal RPE appeared to follow the trajectory of Henle fiber layers, resembling a previously illustrated ‘plume’ on SD-OCT. 14 Migrating RPE cells were seen throughout all retinal layers, even surrounding inner retinal capillaries as in bone spicule degeneration, 39 a phenomenon noted in 11% of eyes in the in vivo cohort.…”

Fell‐Muir Lecture: Fibrillin microfibrils: structural tensometers of elastic tissues?

“…), whilst ADAMTSL4 deficiency causes autosomal recessive isolated ectopia lentis (IEL) and ectopia lentis et pupillae (Collin et al . ). There is also evidence for epithelial involvement in these diseases, reminiscent of the microfibril defects seen at the dermal–epidermal junction in ‘short fibrillinopathies’ caused by fibrillin‐1 mutations.…”

Noninvasive Electroretinographic Procedures for the Study of the Mouse Retina

“…To better evaluate mouse models for genes expressed in the RPE, we adapted an in vivo direct current ERG (dc-ERG) procedure (Kikiwada, 1968) to monitor these responses in anesthetized mice (Wu et al, 2004b). The value of this analysis is supported by subsequent application, where mouse models have been identified in which dc-ERG abnormalities were documented in the face of normal ERG a- and b-waves (e.g., Edwards et al, 2010; Patil et al, 2014; Collin et al, 2015; Saksens et al, 2016). Basic Protocol 2 describes the approach used to record the mouse dc-ERG.…”