Two functional forms of the Meckel-Gruber syndrome protein TMEM67 generated by proteolytic cleavage by ADAMTS9...

Area of Science:

• Cell Biology
• Genetics
• Developmental Biology

Background:

• TMEM67 mutations are a primary cause of Meckel-Gruber syndrome.
• TMEM67 plays roles in ciliary transition zone assembly and Wnt signaling.
• The distinct mechanisms for these two TMEM67 functions were previously unknown.

Purpose of the Study:

• To investigate the functional mechanisms of TMEM67 in ciliogenesis and Wnt signaling.
• To identify how TMEM67 performs its dual roles.
• To understand the clinical significance of TMEM67 function in ciliopathies.

Main Methods:

• Identification of a novel cleavage motif in TMEM67.
• Characterization of TMEM67 cleavage by ADAMTS9.
• Analysis of TMEM67 patient variants in mammalian cell culture and C. elegans.
• Generation and analysis of a non-cleavable TMEM67 mouse model.

Main Results:

• A novel extracellular cleavage motif in TMEM67 was identified, mediated by ADAMTS9.
• Cleavage generates two functional TMEM67 forms: a ciliary form regulating ciliogenesis and a non-cleaved form regulating Wnt signaling.
• Patient variants in the cleavage motif impair cilia structure and function, confirming clinical relevance.
• A non-cleavable TMEM67 mouse model developed ciliopathies but maintained normal Wnt signaling.

Conclusions:

• The cleavage motif is essential for TMEM67's dual functions in ciliogenesis and Wnt signaling.
• This study substantiates the existence of two distinct functional forms of TMEM67.
• Understanding TMEM67 cleavage offers insights into Meckel-Gruber syndrome and ciliopathies.