Molecular Analysis of Mucolipidosis IV

Massachusetts General Hospital, Boston MA

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Abstract

ABSTRACT Mucolipidosis Type IV (MLIV) 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. It is very likely that many patients remain undiagnosed given the heterogeneous clinical spectrum of the disorder. MLIV is caused by mutations in the MCOLN1 gene, which is a 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. 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. Our recent studies have shown that TRPML1 plays a role in chaperone mediated autophagy and lysosomal exocytosis, and we have determined that the TRPML family members can form heteromultimers which modulate channel function. Most significantly, however, we have recently created accurate phenotypic mouse model of MLIV. This mouse model provides, for the first time, a unique system in which to study the pathophysiology of TRPML1 loss in neurons, as well as a model in which to test potential therapies. Armed with this mouse model, we aim to generate a neuronal cell model that will for the first time permit studies of lysosomal function and TRPML1 loss in neuronsl. In addition to this cell culture system, we will use primary neuronal cultures and tissues from the mice to investigate the role of TRPML1 in autophagy and mitochondrial function. Our previous studies show that the TRPML family can form heteromultimers, however, the physiological relevance of these interactions is unknown. Therefore, we plan to create conditional knock-out mouse models for Mcoln2 and Mcoln3 to elucidate their role in MLIV pathophysiology. Lastly, we will continue our characterization of the Mcoln1 mouse model to explore the neuropathological progression of the disease. 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.