scholarly journals The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase

2015 ◽  
Vol 470 (3) ◽  
pp. 331-342 ◽  
Author(s):  
Rob U. Onyenwoke ◽  
Jonathan Z. Sexton ◽  
Feng Yan ◽  
María Cristina Huertas Díaz ◽  
Lawrence J. Forsberg ◽  
...  
Keyword(s):  
Lysosomal Storage Disorder ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Tor Kinase ◽  
Mucolipidosis Iv ◽  
Storage Disorder ◽  
Opening And Closing ◽  
Mucolipidosis Type

The exact mechanisms underlying the lysosomal storage disorder (LSD) mucolipidosis type IV (MLIV) are unclear. In the present study, we provide evidence that mTOR regulates the opening and closing of the lysosomal channel responsible for MLIV through phosphorylation.

scholarly journals Association of luteal cell degeneration and progesterone deficiency with lysosomal storage disorder mucolipidosis type IV in Mcoln1−/− mouse model†

2019 ◽  
Vol 101 (4) ◽  
pp. 782-790 ◽  
Author(s):  
Zidao Wang ◽  
Ahmed E El Zowalaty ◽  
Yuehuan Li ◽  
Christian L Andersen ◽  
Xiaoqin Ye
Keyword(s):  
Corpus Luteum ◽  
Lysosomal Storage Disorder ◽  
Luteal Cell ◽  
Lysosomal Storage ◽  
Cell Degeneration ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Mitochondrial Functions ◽  
Storage Disorder ◽  
Mucolipidosis Type

Abstract Transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1) (MCOLN1/Mcoln1) is a lysosomal counter ion channel. Mutations in MCOLN1 cause mucolipidosis type IV (MLIV), a progressive and severe lysosomal storage disorder with a slow onset. Mcoln1−/− mice recapitulate typical MLIV phenotypes but roles of TRPML1 in female reproduction are unknown. Despite normal mating activities, Mcoln1−/− female mice had reduced fertility at 2 months old and quickly became infertile at 5 months old. Progesterone deficiency was detected on 4.5 days post coitum/gestation day 4.5 (D4.5). Immunohistochemistry revealed TRPML1 expression in luteal cells of wild type corpus luteum (CL). Corpus luteum formation was not impaired in 5–6 months old Mcoln1−/− females indicated by comparable CL numbers in control and Mcoln1−/− ovaries on both D1.5 and D4.5. In the 5–6 months old Mcoln1−/− ovaries, histology revealed less defined corpus luteal cord formation, extensive luteal cell vacuolization and degeneration; immunofluorescence revealed disorganized staining of collagen IV, a basal lamina marker for endothelial cells; Nile Red staining detected lipid droplet accumulation, a typical phenotype of MLIV; immunofluorescence of heat shock protein 60 (HSP60, a mitochondrial marker) and in situ hybridization of steroidogenic acute regulatory protein (StAR, for the rate-limiting step of steroidogenesis) showed reduced expression of HSP60 and StAR, indicating impaired mitochondrial functions. Luteal cell degeneration and impaired mitochondrial functions can both contribute to progesterone deficiency in the Mcoln1−/− mice. This study demonstrates a novel function of TRPML1 in maintaining CL luteal cell integrity and function.

scholarly journals ESCRT-Dependent Cell Death in a Caenorhabditis elegans Model of the Lysosomal Storage Disorder Mucolipidosis Type IV

Genetics ◽  
2015 ◽  
Vol 202 (2) ◽  
pp. 619-638 ◽  
Author(s):  
Julie M. Huynh ◽  
Hope Dang ◽  
Isabel A. Munoz-Tucker ◽  
Marvin O’Ketch ◽  
Ian T. Liu ◽  
...  
Keyword(s):  
Cell Death ◽  
Caenorhabditis Elegans ◽  
Lysosomal Storage Disorder ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Dependent Cell ◽  
Storage Disorder ◽  
Mucolipidosis Type

Mucolipidosis Type IV: Clinical Spectrum and Natural History

PEDIATRICS ◽  
1987 ◽  
Vol 79 (6) ◽  
pp. 953-959
Author(s):  
Naomi Amir ◽  
Joel Zlotogora ◽  
Gideon Bach
Keyword(s):  
Age Of Onset ◽  
Clinical Manifestations ◽  
Psychomotor Retardation ◽  
Clinical Spectrum ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
First Year Of Life ◽  
Developmental Features ◽  
Mucolipidosis Type

The clinical spectrum and developmental features of mucolipidosis type IV, a recessive lysosomal storage disorder, are presented. The evaluation was based on information from the clinical charts and information obtained from the families of 20 patients between the ages of 2 to 17 years. The clinical manifestations of the disease, profound psychomotor retardation and visual impairment, appear during the first year of life. Definitive diagnosis is made by electron microscopy which reveals storage organelles typical of the mucolipidoses. This study details, for the first time, the heterogeneity of the ophthalmologic features, specifically as pertains to the age of onset, degree and clinical course of the corneal opacities, and the retinal involvement. Although the top developmental level was found to be 12 to 15 months in language and motor function, the course of the disease is protracted for some children, who show only a slight improvement, and others, little if any deterioration despite the early infantile onset of the disease. This presentation provides guidelines for the clinical diagnosis of mucolipidosis type IV.

Clinical Spectrum of Mucolipidosis Type IV

PEDIATRICS ◽  
1988 ◽  
Vol 81 (4) ◽  
pp. 602-602
Author(s):  
RAPHAEL WEITZ ◽  
GERTRUDE KOHN
Keyword(s):  
Psychomotor Retardation ◽  
Clinical Spectrum ◽  
Lysosomal Storage ◽  
Motor Delay ◽  
Mucolipidosis Type Iv ◽  
Corneal Clouding ◽  
Type Iv ◽  
History Of ◽  
Corneal Opacities ◽  
Mucolipidosis Type

To the Editor.— We read with interest the presentation by Amir et al1 concerning the clinical spectrum and natural history of mucolipidosis type IV. Based on their experience with 20 patients, they try to provide guidelines for the clinical diagnosis of this lysosomal storage disease. It appears that severe visual impairment (due mainly to corneal opacities, myopia, and retinal degeneration) and psychomotor retardation are the cardinal features of this entity. However, corneal clouding and mild motor delay in their early stages may frequently be missed by even experienced pediatricians and we recently examined a 15-month-old boy who was referred to us for evaluation of a possible congenital myopathy.

Mucolipidosis type IV and the mucolipins

2010 ◽  
Vol 38 (6) ◽  
pp. 1432-1435 ◽  
Author(s):  
Gideon Bach ◽  
David A. Zeevi ◽  
Ayala Frumkin ◽  
Aviram Kogot-Levin
Keyword(s):  
Cellular Localization ◽  
Transient Receptor Potential ◽  
Physiological Role ◽  
Receptor Potential ◽  
Lysosomal Storage ◽  
Additional Function ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Early Endosomes ◽  
Mucolipidosis Type

MLIV (mucolipidosis type IV) is a neurodegenerative lysosomal storage disorder caused by mutations in MCOLN1, a gene that encodes TRPML1 (mucolipin-1), a member of the TRPML (transient receptor potential mucolipin) cation channels. Two additional homologues are TRPML2 and TRPML3 comprising the TRPML subgroup in the TRP superfamily. The three proteins play apparently key roles along the endocytosis process, and thus their cellular localization varies among the different group members. Thus TRPML1 is localized exclusively to late endosomes and lysosomes, TRPML2 is primarily located in the recycling clathrin-independent GPI (glycosylphosphatidylinositol)-anchored proteins and early endosomes, and TRPML3 is primarily located in early endosomes. Apparently, all three proteins' main physiological function underlies Ca2+ channelling, regulating the endocytosis process. Recent findings also indicate that the three TRPML proteins form heteromeric complexes at least in some of their cellular content. The physiological role of these complexes in lysosomal function remains to be elucidated, as well as their effect on the pathophysiology of MLIV. Another open question is whether any one of the TRPMLs bears additional function in channel activity

Mucolipidosis type IV

Neurology ◽  
1998 ◽  
Vol 51 (2) ◽  
pp. 565-569 ◽  
Author(s):  
K. P. Frei ◽  
N. J. Patronas ◽  
K. E. Crutchfield ◽  
G. Altarescu ◽  
R. Schiffmann
Keyword(s):  
Corpus Callosum ◽  
Clinical Findings ◽  
Unknown Etiology ◽  
Lysosomal Storage ◽  
Mri Findings ◽  
Mucolipidosis Type Iv ◽  
Corneal Clouding ◽  
Type Iv ◽  
Cranial Mri ◽  
Mucolipidosis Type

Objective: The objective of this study is to characterize the brain abnormalities on head MRI of patients with mucolipidosis type IV.Background: Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology. Patients develop corneal clouding, retinal degeneration, spastic quadriparesis, and mental retardation. Patients with this disorder have not been studied systematically.Methods: We studied prospectively 15 consecutive patients with mucolipidosis type IV using cranial MRI.Results: Fourteen patients with these typical clinical findings had a hypoplastic corpus callosum with absent rostrum and a dysplastic or absent splenium, signal abnormalities on T1-weighted head MRI images in the white matter, and increased ferritin deposition in the thalamus and basal ganglia. Atrophy of the cerebellum and cerebrum was observed in older patients, which may reflect disease progression. One patient with a mild clinical variant had a normal corpus callosum.Conclusion: Patients with mucolipidosis type IV have characteristic cranial MRI findings that suggest that this disorder causes both developmental and neurodegenerative abnormalities.

scholarly journals Membrane traffic and turnover in TRP-ML1–deficient cells: a revised model for mucolipidosis type IV pathogenesis

2008 ◽  
Vol 205 (6) ◽  
pp. 1477-1490 ◽  
Author(s):  
Mark T. Miedel ◽  
Youssef Rbaibi ◽  
Christopher J. Guerriero ◽  
Grace Colletti ◽  
Kelly M. Weixel ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Degradation Kinetics ◽  
Density Lipoprotein ◽  
Membrane Traffic ◽  
Cumulative Effect ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Kinetics Of ◽  
Mucolipidosis Type

The lysosomal storage disorder mucolipidosis type IV (MLIV) is caused by mutations in the transient receptor potential–mucolipin-1 (TRP-ML1) ion channel. The “biogenesis” model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes by regulating interactions between late endosomes and lysosomes. This model is based on observed lipid trafficking delays in MLIV patient fibroblasts. Because membrane traffic aberrations may be secondary to lipid buildup in chronically TRP-ML1–deficient cells, we depleted TRP-ML1 in HeLa cells using small interfering RNA and examined the effects on cell morphology and postendocytic traffic. TRP-ML1 knockdown induced gradual accumulation of membranous inclusions and, thus, represents a good model in which to examine the direct effects of acute TRP-ML1 deficiency on membrane traffic. Ratiometric imaging revealed decreased lysosomal pH in TRP-ML1–deficient cells, suggesting a disruption in lysosomal function. Nevertheless, we found no effect of TRP-ML1 knockdown on the kinetics of protein or lipid delivery to lysosomes. In contrast, by comparing degradation kinetics of low density lipoprotein constituents, we confirmed a selective defect in cholesterol but not apolipoprotein B hydrolysis in MLIV fibroblasts. We hypothesize that the effects of TRP-ML1 loss on hydrolytic activity have a cumulative effect on lysosome function, resulting in a lag between TRP-ML1 loss and full manifestation of MLIV.

scholarly journals Mucolipidosis Type IV: The Effect of Increased Lysosomal pH on the Abnormal Lysosomal Storage

2009 ◽  
Vol 65 (6) ◽  
pp. 686-690 ◽  
Author(s):  
Aviram Kogot-Levin ◽  
Marsha Zeigler ◽  
Asher Ornoy ◽  
Gideon Bach
Keyword(s):  
Lysosomal Storage ◽  
Lysosomal Ph ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Mucolipidosis Type

scholarly journals Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV

EMBO Reports ◽  
2015 ◽  
Vol 17 (2) ◽  
pp. 266-278 ◽  
Author(s):  
Soonhong Park ◽  
Malini Ahuja ◽  
Min Seuk Kim ◽  
G Cristina Brailoiu ◽  
Archana Jha ◽  
...  
Keyword(s):  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Lysosomal Storage ◽  
Mucolipidosis Type Iv ◽  
Type Iv ◽  
Mucolipidosis Type
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