Retinal Function in Mucolipidosis IV

Abraham, Fabian A.; Brand, Natan; Blumenthal, Michael; Merin, Saul

doi:10.1159/000309589

Cited by 14 publications

(11 citation statements)

References 10 publications

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“…The current study systematically investigated the clinical and natural history features of the largest cohort of patients with MLIV published to date. 34 Similar progressive retinal alteration is also seen in tapetoretinal dystrophy and in a few cases of mucopoly-saccharidoses. The disease is usually manifested by visual impairment due to corneal opacity and retinal dystrophy, psychomotor retardation consisting of delayed milestones, hypotonia that gradually progressed to spasticity, and bilateral pyramidal tract signs.…”

Section: Results Patient History and Clinical Characteristicsmentioning

confidence: 78%

The neurogenetics of mucolipidosis type IV

Altarescu

Sun²,

Moore³

et al. 2002

Neurology

165

179

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Section: Results Patient History and Clinical Characteristicsmentioning

confidence: 78%

The neurogenetics of mucolipidosis type IV

Altarescu

Sun²,

Moore³

et al. 2002

Neurology

165

179

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“…Although there are only a few longitudinal studies of eye pathology in MLIV, they demonstrate progressive worsening of ophthalmic features in patients. 2,4,51 Data in Mcoln1 À/À mice revealed that thinning of photoreceptor layer and ERG responses were not progressive in the course of disease. Nevertheless, despite the altered time course, recapitulation of the photoreceptor and optic nerve pathological features of MLIV in Mcoln1 À/À mice makes it a good model for preclinical gene therapy testing for this devastating disease.…”

Section: Discussionmentioning

confidence: 97%

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

Grishchuk

Stember

Matsunaga

et al. 2016

The American Journal of Pathology

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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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“…Even if some of the less severely affected patients do not display clear psychomotor disabilities, the ocular disturbances may still be present [31, 32]. Along with bilateral corneal opacity and optic atrophy, the retinal degeneration results in complete blindness by the end of the first decade of life [25–28, 33, 34]. Patients have also been reported to exhibit other ocular disturbances including pain, strabismus, bouts of excessive tearing and conjunctivitis, and occasional photophobia [26, 35].…”

Section: Mucolipidosis Type Iv: a Clinical Perspectivementioning

confidence: 99%

The role of TRPMLs in endolysosomal trafficking and function

Venkatachalam¹,

Wong²,

Zhu³

2015

Cell Calcium

178

151

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Members of the Transient Receptor Potential-Mucolipin (TRPML) constitute a family of evolutionarily conserved cation channels that function predominantly in endolysosomal vesicles. Whereas loss-of-function mutations in human TRPML1 were first identified as being causative for the lysosomal storage disease, Mucolipidosis type IV, most mammals also express two other TRPML isoforms called TRPML2 and TRPML3. All three mammalian TRPMLs as well as TRPML related genes in other species including C. elegans and Drosophila exhibit overlapping functional and biophysical properties. The functions of TRPML proteins include roles in vesicular trafficking and biogenesis, maintenance of neuronal development, function, and viability, and regulation of intracellular and organellar ionic homeostasis. Biophysically, TRPML channels are non-selective cation channels exhibiting variable permeability to a host of cations including Na+, Ca2+, Fe2+, and Zn2+, and are activated by a phosphoinositide species, PI(3,5)P2, that is mostly found in endolysosomal membranes. Here, we review the functional and biophysical properties of these enigmatic cation channels, which represent the most ancient and archetypical TRP channels.

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Retinal Function in Mucolipidosis IV

Cited by 14 publications

References 10 publications

The neurogenetics of mucolipidosis type IV

The neurogenetics of mucolipidosis type IV

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

The role of TRPMLs in endolysosomal trafficking and function

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