Molecular Analysis of Mucolipidosis IV

Massachusetts General Hospital, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Mucolipidosis Type IV (MLIV; MIM 252650) is a developmental disorder that is characterized by severe neurologic and ophthalmologic abnormalities. Classified as a lysosomal storage disorder, it is progressive and usually presents during the first year of life with mental retardation, corneal opacities, and delayed motor milestones. Most MLIV children are developmentally arrested at 15 months in language and motor function, and are eventually totally blind as the result of retinal degeneration. The majority of patients diagnosed to date are of Ashkenazi Jewish descent and the carrier frequency in this population is 1 in 100. It is very likely that many patients remain undiagnosed given the heterogeneous clinical spectrum of the disorder. Most MLIV patients die at a young age and there is currently no treatment for this tragic disorder. [unreadable] [unreadable] Recently, we reported the successful cloning of the MLIV gene, MCOLN1. MCOLN1 is a new member of the transient receptor potential (TRP) cation channel gene family. MCOLN1 encodes a protein called mucolipin-1 that, like the other TRP genes, has six predicted transmembrane domains and a channel pore. [unreadable] [unreadable] MCOLN1, together with MCOLN2 and MCOLN3, two homologous genes that map to human chromosome 1, constitute the TRPML subfamily. The identification of mutations in MCOLN1 represents the first example of a neurological disease caused by a TRP-related channel. Kinetic studies have demonstrated that the abnormal storage in MLIV cells stems from the abnormal endocytosis of membrane components. Very recently, we have shown that mucolipin-1 is a calcium permeable cation channel that plays a major role in calcium transport across lysosomal membranes, suggesting a crucial role in late endosomal/lysosomal trafficking. The goal of the current grant is to build on our previous work and determine the cellular function of the mucolipin gene family using animal models, cellular models, and gene expression and pathway analysis in order to understand MLIV pathogenesis. In the long-term these studies will contribute to the fundamental understanding of normal cellular trafficking and lysosomal function, and ultimately to the hope of MLIV patients for an effective treatment aimed at abolishing the abnormal cellular storage in this devastating disease. [unreadable] [unreadable]