TY - JOUR
T1 - Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV
AU - Grishchuk, Yulia
AU - Stember, Katherine G.
AU - Matsunaga, Aya
AU - Olivares, Ana M.
AU - Cruz, Nelly M.
AU - King, Victoria E.
AU - Humphrey, Daniel M.
AU - Wang, Shirley L.
AU - Muzikansky, Alona
AU - Betensky, Rebecca A.
AU - Thoreson, Wallace B.
AU - Haider, Neena
AU - Slaugenhaupt, Susan A.
N1 - Funding Information:
Supported by an ML4 Foundation grant (Y.G. and S.A.S.), a Research to Prevent Blindness Senior Scientific Investigator Award (W.B.T.), NIH National Eye Institute core grant (P30EY003790), NIH Award 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic health care centers. Statistical analysis was conducted with support from Harvard NeuroDiscovery Center and Harvard Catalyst (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH Award 8UL1TR000170-05, and financial contributions from Harvard University and its affiliated academic health care centers). SERI electron microscopy core is supported through an NIH NEI Core grant (P30EY003790). We thank Philip Seifert (Schepen''s Eye Research Institute electron microscopy core) for electron microscopy sample preparation and image acquisition, Oscar Morales for conducting electroretinographic recording procedures, and Dr. Igor Nasonkin for critical reading of the manuscript and useful discussion.
Publisher Copyright:
© 2016 American Society for Investigative Pathology.
PY - 2016/1/1
Y1 - 2016/1/1
N2 - 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.
AB - 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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U2 - 10.1016/j.ajpath.2015.09.017
DO - 10.1016/j.ajpath.2015.09.017
M3 - Article
C2 - 26608452
AN - SCOPUS:84955512389
SN - 0002-9440
VL - 186
SP - 199
EP - 209
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -