title: Disruption of murine Adamtsl4 results 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Gayle B
authors.initials: GB
authors.lastname: Collin
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hubmacher
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Charette
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Wanda L
authors.initials: WL
authors.lastname: Hicks
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stone
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA, Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA and.
authors.forename: Minzhong
authors.initials: M
authors.lastname: Yu
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Krebs
authors.affiliation: Cole Eye Institute, Cleveland Clinic, Cleveland, OH, USA, Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA and Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Peachey
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA.
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, USA, patsy.nishina@jax.org.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000502:physiology; D000071121:ADAMTS4 Protein; D000818:Animals; D058452:Axial Length, Eye; D002454:Cell Differentiation; D018389:Codon, Nonsense; D003094:Collagen / Q000235:genetics; D004195:Disease Models, Animal; D004479:Ectopia Lentis / Q000235:genetics* / Q000473:pathology; D024021:Fibril-Associated Collagens; D005786:Gene Expression Regulation; D006720:Homozygote; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D011348:Procollagen N-Endopeptidase / Q000235:genetics* / Q000502:physiology; D011680:Pupil; D011681:Pupil Disorders / Q000235:genetics* / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000166:cytology* / Q000473:pathology
chemical_list: D018389:Codon, Nonsense; D024021:Fibril-Associated Collagens; C425332:col19a1 protein, mouse; D003094:Collagen; D051722:ADAM Proteins; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein