2. Academic Validation
  3. Disease-associated mutations of claudin-19 disrupt retinal neurogenesis and visual function

Disease-associated mutations of claudin-19 disrupt retinal neurogenesis and visual function

  • Commun Biol. 2019 Mar 25:2:113. doi: 10.1038/s42003-019-0355-0.
Shao-Bin Wang # 1 2 3,  Tao Xu # 1 2 4,  Shaomin Peng 4,  Deepti Singh 1 2 5,  Maryam Ghiassi-Nejad 1 2,  Ron A Adelman 2,  Lawrence J Rizzolo 1 2
Affiliations

Affiliations

  • 1 1Department of Surgery, Yale University, PO Box 208062, New Haven, CT USA.
  • 2 2Department of Ophthalmology, Yale University, 40 Temple Street, New Haven, CT USA.
  • 3 4Present Address: Center for Advanced Vision Science, Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908 USA.
  • 4 3Aier School of Ophthalmology, Central South University, 198 Furong Middle Ave Section 2, Tianxin District, Changsha, China.
  • 5 5Present Address: Department of Ophthalmology, The Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford St., Boston, MA 02114 USA.
  • # Contributed equally.
PMID: 30937396 DOI: 10.1038/s42003-019-0355-0
Abstract

Mutations of claudin-19 cause Familial Hypomagnesaemia and Hypercalciuria, Nephrocalcinosis with Ocular Involvement. To study the ocular disease without the complications of the kidney disease, naturally occurring point mutations of human CLDN19 were recreated in human induced pluripotent cells or overexpressed in the retinae of newborn mice. In human induced pluripotent cells, we show that the mutation affects retinal neurogenesis and maturation of retinal pigment epithelium (RPE). In mice, the mutations diminish the P1 wave of the electroretinogram, activate Apoptosis in the outer nuclear layer, and alter the morphology of bipolar cells. If mice are given 9-cis-retinal to counter the loss of retinal isomerase, the P1 wave is partially restored. The ARPE19 cell line fails to express claudin-19. Exogenous expression of wild type, but not mutant claudin-19, increases the expression of RPE signature genes. Mutated claudin-19 affects multiple stages of RPE and retinal differentiation through its effects on multiple functions of the RPE.

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