期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 186, 期 1, 页码 199-209出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2015.09.017
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资金
- ML4 Foundation
- Research to Prevent Blindness Senior Scientific Investigator Award
- NIH National Eye Institute [P30EY003790]
- NIH [8UL1TR000170-05]
- Harvard University
- Harvard NeuroDiscovery Center and Harvard Catalyst (National Center for Advancing Translational Sciences, NIH) [8UL1TR000170-05]
- NIH NEI Core grant [P30EY003790]
Mucolipidosis IV is a debilitating developmental Lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, Leading to blindness by the second decade of Life. Mucolipidosis IV is caused by Loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1(-/-) mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1(-/-) retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1(-/-) mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1(-/-) mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin-1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV.
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