Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV

Yulia Grishchuk, Katherine G. Stember, Aya Matsunaga, Ana M. Olivares, Nelly M. Cruz, Victoria E. King, Daniel M. Humphrey, Shirley L. Wang, Alona Muzikansky, Rebecca A. Betensky, Wallace B. Thoreson, Neena Haider, Susan A. Slaugenhaupt

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)199-209
Number of pages11
JournalAmerican Journal of Pathology
Volume186
Issue number1
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Grishchuk, Y., Stember, K. G., Matsunaga, A., Olivares, A. M., Cruz, N. M., King, V. E., Humphrey, D. M., Wang, S. L., Muzikansky, A., Betensky, R. A., Thoreson, W. B., Haider, N., & Slaugenhaupt, S. A. (2016). Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV. American Journal of Pathology, 186(1), 199-209. https://doi.org/10.1016/j.ajpath.2015.09.017