title: Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV.
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.
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts. Electronic address: ygrishchuk@mgh.harvard.edu.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Grishchuk
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Stember
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Aya
authors.initials: A
authors.lastname: Matsunaga
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Olivares
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
authors.forename: Nelly M
authors.initials: NM
authors.lastname: Cruz
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: King
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Humphrey
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Wang
authors.affiliation: Massachusetts General Hospital Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Alona
authors.initials: A
authors.lastname: Muzikansky
authors.affiliation: Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Betensky
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Thoreson
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts.
authors.forename: Neena
authors.initials: N
authors.lastname: Haider
authors.affiliation: Department of Neurology, Center for Human Genetic Research, Harvard Medical School, Boston, Massachusetts.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Slaugenhaupt
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004596:Electroretinography; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000150:complications / Q000473:pathology*; D009900:Optic Nerve / Q000473:pathology*; D058499:Retinal Dystrophies / Q000473:pathology*; D041623:Tomography, Optical Coherence; D050051:Transient Receptor Potential Channels / Q000172:deficiency / Q000235:genetics
chemical_list: C512321:Mcoln1 protein, mouse; D050051:Transient Receptor Potential Channels