Sarah E Seese1,2, Brett Deml1,2,3, Sanaa Muheisen1, Elena Sorokina1, Elena V Semina1,2,4,5. 1. Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 2. Cell Biology, Neurobiology and Anatomy, The Medical College of Wisconsin, Milwaukee, Wisconsin, USA. 3. PreventionGenetics, Marshfield, Wisconsin, USA. 4. Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, Wisconsin, USA. 5. Children's Research Institute, Medical College of Wisconsin, Children's of Wisconsin, Milwaukee, Wisconsin, USA.
Abstract
BACKGROUND: The male-abnormal 21 like (MAB21L) genes are important in human ocular development. Homozygous loss of MAB21L1 leads to corneal dystrophy in all affected individuals along with cataracts and buphthalmos in some. The molecular function and downstream pathways of MAB21L factors are largely undefined. RESULTS: We generated the first mab21l1 zebrafish mutant carrying a putative loss-of-function allele, c.107delA p.(Lys36Argfs*7). At the final stages of embryonic development, homozygous mab21l1c.107delA fish displayed enlarged anterior chambers and corneal thinning which progressed with age. Additional studies revealed increased cell death in the mutant corneas, transformation of the cornea into a skin-like epithelium, and progressive lens degeneration with development of fibrous masses in the anterior chamber. RNA-seq of wild-type and mutant ocular transcriptomes revealed significant changes in expression of several genes, including irf1a and b, stat1, elf3, krt17, tlr9, and loxa associated with immunity and/or corneal function. Abnormal expression of lysyl oxidases have been previously linked with corneal thinning, fibrosis, and lens defects in mammals, suggesting a role for loxa misexpression in the progressive mab21l1c.107delA eye phenotype. CONCLUSIONS: Zebrafish mab21l1 is essential for normal corneal development, similar to human MAB21L1. The identified molecular changes in mab21l1c.107delA mutants provide the first clues about possible affected pathways.
BACKGROUND: The male-abnormal 21 like (MAB21L) genes are important in human ocular development. Homozygous loss of MAB21L1 leads to corneal dystrophy in all affected individuals along with cataracts and buphthalmos in some. The molecular function and downstream pathways of MAB21L factors are largely undefined. RESULTS: We generated the first mab21l1 zebrafish mutant carrying a putative loss-of-function allele, c.107delA p.(Lys36Argfs*7). At the final stages of embryonic development, homozygous mab21l1c.107delA fish displayed enlarged anterior chambers and corneal thinning which progressed with age. Additional studies revealed increased cell death in the mutant corneas, transformation of the cornea into a skin-like epithelium, and progressive lens degeneration with development of fibrous masses in the anterior chamber. RNA-seq of wild-type and mutant ocular transcriptomes revealed significant changes in expression of several genes, including irf1a and b, stat1, elf3, krt17, tlr9, and loxa associated with immunity and/or corneal function. Abnormal expression of lysyl oxidases have been previously linked with corneal thinning, fibrosis, and lens defects in mammals, suggesting a role for loxa misexpression in the progressive mab21l1c.107delA eye phenotype. CONCLUSIONS: Zebrafish mab21l1 is essential for normal corneal development, similar to human MAB21L1. The identified molecular changes in mab21l1c.107delA mutants provide the first clues about possible affected pathways.
Authors: Cláudia C Miranda; Tiago G Fernandes; Jorge F Pascoal; Simone Haupt; Oliver Brüstle; Joaquim M S Cabral; Maria Margarida Diogo Journal: Biotechnol J Date: 2015-04-28 Impact factor: 4.677
Authors: Kathryn E Hendee; Elena A Sorokina; Sanaa S Muheisen; Linda M Reis; Rebecca C Tyler; Vujica Markovic; Goran Cuturilo; Brian A Link; Elena V Semina Journal: Hum Mol Genet Date: 2018-05-15 Impact factor: 6.150