LYSOSOMAL ENZYMES AND ASSOCIATED HUMAN GENETIC DISEASES

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There are over 40 known lysosomal enzymes and accessory proteins that function in concert to degrade complex molecules into simple components. The biomedical importance of these proteins is underscored by the spectrum of human genetic diseases known to result from mutations in 32 different lysosomal proteins. Compelling evidence indicates that additional lysosomal proteins not yet identified exist, and it is highly likely that defects in some of these underlie hereditary diseases of unknown etiology. The overall goal of this proposal is to develop and implement a systematic approach that will result in the identification and characterization of lysosomal proteins and their role in human genetic diseases. This approach relies on the finding that most lysosomal proteins contain a common post-translational modification, the mannose 6-phosphate (Man-6-P) recognition marker, which distinguishes them from other types of proteins. There are four specific aims. Specific aim 1 is to identify the spectrum of Man-6-P glycoproteins present in human brain. This will identify a number of novel human lysosomal proteins and create a two-dimensional reference database of human Man-6-P glycoproteins separated by isoelectric point and molecular weight. Specific aim 2 is to identify lysosomal proteins that are defective in human genetic diseases of unknown etiology by comparing the spectrum of Man-6-P glycoproteins present in patient samples with normal controls. Specific Aim 3 is to use genomic methods to identify candidate diseases that may be associated with the genes encoding novel lysosomal proteins. Specific Aim 4 is to confirm the involvement of lysosomal proteins in diseases of unknown etiology by identifying the molecular defect in the corresponding genes. The proposed studies are highly likely to lead to the discovery of the molecular basis for multiple human hereditary diseases, and will be a critical step that will enable definitive diagnosis and prenatal testing. In addition, these studies will result in the characterization of previously unidentified human lysosomal proteins and will provide fundamental contributions towards understanding the role of lysosomes in biology and medicine.