Identification of the gene causing mucolipidosis type IV

Abstract

Mucolipidosis type IV (MLIV) is an autosomal recessive, neurodegenerative, lysosomal storage disorder characterized by psychomotor retardation and ophthalmological abnormalities including corneal opacities, retinal degeneration and strabismus. Most patients reach a maximal developmental level of 12?15 months. The disease was classified as a mucolipidosis following observations by electron microscopy indicating the lysosomal storage of lipids together with water-soluble, granulated substances. Over 80% of the MLIV patients diagnosed are Ashkenazi Jews, including severely affected and mildly affected patients. The gene causing MLIV was previously mapped to human chromosome 19p13.2-13.3 in a region of approximately 1 cM (ref. 7). Haplotype analysis in the MLIV gene region of over 70 MLIV Ashkenazi chromosomes indicated the existence of two founder chromosomes among 95% of the Ashkenazi MLIV families: a major haplotype in 72% and a minor haplotype in 23% of the MLIV chromosomes (ref. 7, and G.B., unpublished data). The remaining 5% are distinct haplotypes found only in single patients. The basic metabolic defect causing the lysosomal storage in MLIV has not yet been identified. Thus, positional cloning was an alternative to identify the MLIV gene. We report here the identification of a new gene in this human chromosomal region in which MLIV-specific mutations were identified.

Structure of mammalian endolysosomal TRPML1 channel in nanodiscs

“…This lipid isoform-dependent gating property defines the compartment specific channel activity of TRPML1. In human, loss-of-function mutations in TRPML1 are the direct cause of Mucolipidosis type IV (MLIV), an autosomal recessive lysosomal storage disease characterized by abnormal neurodevelopment, retinal degeneration and iron-deficiency anemia 3-6 . Due to its direct linkage to MLIV disease, TRPML1 has been a potential target for small molecule therapeutics and several synthetic small molecule agonists have been developed 12,20 .…”

“… Transient receptor potential mucolipin 1 (TRPML1) is an endo/lysosomal cation channel ubiquitously expressed in mammalian cells 1,2 and its loss-of-function mutations are the direct cause of Type IV mucolipidosis (MLIV), an autosomal recessive lysosomal storage disease 3-6 . Here we present the single particle cryo-electron microscopy (cryo-EM) structure of the mouse TRPML1 channel embedded in nanodiscs.…”

A novel mode of TRPML3 regulation by extracytosolic pH absent in the varitint-waddler phenotype

“…The TRPML subfamily has three members, TRPML1, TRPML2 and TRPML3. Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (Bargal et al, 2000;Kiselyov et al, 2007). TRPML1 is a lysosomal channel (Manzoni et al, 2004) that when mutated or deleted impairs mainly lysosomal recycling (Fares and Greenwald, 2001;Hersh et al, 2002).…”

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

“…Eventually, mutations in the TRPML1 (MCOLN1) gene were discovered as the genetic cause of MLIV [6][7][8] . In recent years, TRPML1 has been characterized using electrophysiological tools and its basic cation channel properties have been investigated [9][10][11][12][13][14][15][16][17][18][19] , its protein-protein interaction network has been explored [20][21][22][23][24] , and knockout mouse models have been generated and investigated [25][26][27][28] .…”

“…However, effective treatment options for MLIV patients are still missing. Unfortunately, many patients carry mutations that introduce premature stop signals in the TRPML1 gene [6][7][8] . As a result, the TRPML1 protein is completely absent, or abnormally short and lacks the ion conducting pore between TMD5 and TMD6.…”