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

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $420,063

## Abstract

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.

## Key facts

- **NIH application ID:** 10902075
- **Project number:** 5R01HD109346-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Ming Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $420,063
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902075

## Citation

> US National Institutes of Health, RePORTER application 10902075, Characterization of TMEM251 that causes a new type of severe lysosome storage disease (5R01HD109346-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10902075. Licensed CC0.

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