Characterization of TMEM251 that causes a new type of severe lysosome storage disease

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The lysosome is an essential organelle to recycle materials delivered by endocytosis and autophagy. Inborn genetic defects affecting the lysosome cause debilitating and fatal lysosomal storage diseases (LSDs, ~70 in humans). One severe form of LSD, the I-cell disease, leads to skeletal dysplasia, short stature, cardiomegaly, and death in the first decade. It is caused by mutations in the GlcNAc-1-phosphotransferase enzyme (GNPT), which functions at the cis- Golgi to label lysosome enzymes with sorting signal mannose-6-phosphate (M6P). Missing M6P leads to the secretion of most lysosomal enzymes and defective lysosomes. In early 2021, a new type of severe LSD similar to the I-cell disease was reported. Patients will develop skeletal dysplasia, short stature, cardiac defects, and some die in early childhood. Their lysosomal enzymes are also secreted into the plasma. It is caused by mutations in TMEM251, but the cellular function of TMEM251 and the molecular mechanism for the disease remain to be addressed. In a genome-wide CRISPR knockout screen to identify genes critical for the degradation of human lysosome membrane proteins, we independently discovered TMEM251 to be essential for lysosome function. Knocking out TM251 leads to lysosomal dysfunction due to the secretion of unprocessed lysosomal enzymes. Consequently, lysosomes accumulate numerous undigested materials such as autophagic bodies and endocytic vesicles. Consistent with human pathology, knocking out TM251 in Zebrafish leads to cardiac defects and skeletal dysplasia. We hypothesize that TM251 functions in the M6P biogenesis pathway of lysosomal enzymes. We will pursue three specific aims to characterize the role of TM251 in lysosome biogenesis. In aim 1, we will characterize membrane topology, localization, and oligomerization of TM251. In aim 2, we will dissect the relationship between TM251 and the GNPT complex at both cellular and organismal levels. In aim 3, we will study the signaling cascade that leads to lysosome upregulation after knocking out TM251. Our findings will uncover the role of TM251 in the M6P biogenesis and provide a molecular mechanism for a new lysosome storage disease that severely affects child health.