Hereditary sensory and autonomic neuropathy type 9 (HSAN9) is a rare neurological disorder caused by mutations in the TECPR2 gene, which encodes the multi-domain protein TECPR2 (Tectonin β-propeller repeat-containing protein 2). While the carboxy-terminal region of TECPR2 is known for its role in autophagosome targeting, the function of its amino terminal WD domain has remained unknown.
In this study, we identified the function of TECPR2 in collagen hydroxylation and trafficking. We show that the WD domain of TECPR2 interacts with the BLOC-1 complex to regulate the cellular iron pool through transferrin recycling. This regulation is essential for proper hydroxylation of collagen, a key step in its maturation and extracellular export.
In Tecpr2-deficient mice, we observed significantly reduced collagen levels across tissues, accompanied by impaired respiration and respiratory alkalosis. Remarkably, restoring collagen hydroxylation was sufficient to correct these physiological abnormalities. These findings links altered collagen processing due to loss of Tecpr2 and high mortality due to respiratory failure reported in HSAN9 patients.
Our work sheds light on the role of WD domain of Tecpr2 in collagen processing and its link to lung physiology.