The neurogenetics of mucolipidosis type IV

Altarescu, Gheona; Sun, Mei; Moore, Dennis F.; Smith, Janine A.; Wiggs, Edythe; Solomon, Beth; Patronas, Nicholas J.; Frei, Karen; Gupta, Smriti; Kaneski, Christine R.; Quarrell, Owj; Slaugenhaupt, Susan; Goldin, Ehud; Schiffmann, Raphael

doi:10.1212/wnl.59.3.306

Cited by 165 publications

(190 citation statements)

References 37 publications

Supporting

Mentioning

184

Contrasting

Unclassified

Order By: Relevance

“…We focused on several MLIV causing point mutants described in the literature with either unknown subcellular localization (R403C, Y436C, V446L, V447P, S456L) 3,7,29,31,32 , or mutant isoforms reported to show partial localization on endosomes and lysosomes, that is, F408D, an in-frame mutant that lacks one amino acid, and F465L 7,30 (Fig. 1a, Supplementary Fig.…”

Section: Subcellular Localization Of MLIV Causing Trpml1 Mutantsmentioning

confidence: 99%

“…Constitutive achlorhydria associated with a secondary elevation of serum gastrin levels is also a characteristic feature of the disease. Iron deficiency anaemia, secondary to the achlorhydria, is another phenotypic feature which occurs in about 50% of the patients [2][3][4][5] .…”

mentioning

confidence: 99%

“…As a result, the TRPML1 protein is completely absent, or abnormally short and lacks the ion conducting pore between TMD5 and TMD6. Some patients however carry single point mutations which do not destroy the open reading frame 3,7,[29][30][31][32] . While some of these appear to be largely mislocalized, others retain a predominant lysosomal localization.…”

mentioning

confidence: 99%

See 2 more Smart Citations

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

et al. 2014

View full text Add to dashboard Cite

Section: Subcellular Localization Of MLIV Causing Trpml1 Mutantsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

et al. 2014

View full text Add to dashboard Cite

“…retinal degeneration, sensitivity to light, and strabismus (1)(2)(3). Analysis of various cell types from MLIV patients by electron microscopy revealed the presence of enlarged vacuolar structures.…”

mentioning

confidence: 99%

Identification of the Penta-EF-hand Protein ALG-2 as a Ca2+-dependent Interactor of Mucolipin-1

Vergarajaúregui

Martina

Puertollano

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Loss of function mutations in mucolipin-1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a recessive lysosomal storage disease characterized by severe neurological and ophthalmological abnormalities. MCOLN1 is an ion channel that regulates membrane transport along the endolysosomal pathway. It has been suggested that MCOLN1 participates in several Ca 2؉ -dependent processes, including fusion of lysosomes with the plasma membrane, fusion of late endosomes and autophagosomes with lysosomes, and lysosomal biogenesis. Here, we searched for proteins that interact with MCOLN1 in a Ca 2؉ -dependent manner. We found that the penta-EF-hand protein ALG-2 binds to the NH-terminal cytosolic tail of MCOLN1. The interaction is direct, strictly dependent on Ca 2؉ , and mediated by a patch of charged and hydrophobic residues located between MCOLN1 residues 37 and 49. We further show that MCOLN1 and ALG-2 co-localize to enlarged endosomes induced by overexpression of an ATPase-defective dominantnegative form of Vps4B (Vps4B E235Q ). In agreement with the proposed role of MCOLN1 in the regulation of fusion/fission events, we found that overexpression of MCOLN1 caused accumulation of enlarged, aberrant endosomes that contain both early and late endosome markers. Interestingly, aggregation of abnormal endosomes was greatly reduced when the ALG-2-binding domain in MCOLN1 was mutated, suggesting that ALG-2 regulates MCOLN1 function. Overall, our data provide new insight into the molecular mechanisms that regulate MCOLN1 activity. We propose that ALG-2 acts as a Ca 2؉ sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway.

show abstract

“…Other symptoms include characteristic opthalmological abnormalities (Online Mendelian Inheritance in Man). 3,5,6 ML IV is caused by loss of function mutations in the MCOLN1 gene. 8 The gene has been mapped to chromosome 19 and codes for a potential membrane channel.…”

mentioning

confidence: 99%

Rapid One-Step Carrier Detection Assay of Mucolipidosis IV Mutations in the Ashkenazi Jewish Population

Hantash

Olson

Anderson

et al. 2006

The Journal of Molecular Diagnostics

View full text Add to dashboard Cite

Two mutations in the MCOLN1 mucolipidosis IV (ML IV) gene represent ϳ95% of the mutations in Ashkenazi-Jewish patients with ML IV. The mutations , a splice site mutation (IVS3-2A>G) and an ϳ6.4-kb deletion (511del6434) , account for 72% and 23% of ML IV alleles in this population , respectively. An automated high-throughput assay was developed using the 5-nuclease (TaqMan) method for the simultaneous detection of both mutations in a single reaction. Three fluorescent probes specifically detected wild-type , IVS3-2A>G , and 511del6434 alleles in each reaction real-time. Data collected were automatically analyzed , and genotype results were uploaded into a laboratory information management system. The assay was validated using genomic controls , demonstrating high robustness and accuracy. Carrier screening of 10 ,527 samples revealed 77 heterozygote carriers of IVS3-2A>G , 25 heterozygote carriers of 511del6434 , and two compound heterozygote of both mutant alleles. The frequency of mutated alleles was 0.73% for IVS3-2A>G and 0.24% for 511del6434. The combined carrier frequency was 1:103 with predicted disease incidence of 1:42 ,436 individuals in this population , slightly lower than previously described frequencies. This automated high-throughput assay is labor saving , because two mutations can be detected in a single reaction. The method has potential for use in other assays requiring simultaneous detection of two mutations.

show abstract

The neurogenetics of mucolipidosis type IV

Abstract: MLIV is both a developmental and a degenerative disorder. The presentation as a cerebral palsy-like encephalopathy may delay diagnosis.

Cited by 165 publications

References 37 publications

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV

Identification of the Penta-EF-hand Protein ALG-2 as a Ca2+-dependent Interactor of Mucolipin-1

Rapid One-Step Carrier Detection Assay of Mucolipidosis IV Mutations in the Ashkenazi Jewish Population

Contact Info

Product

Resources

About