All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding

Area of Science:

• Molecular Cell Biology
• Genetics and Disease Mechanisms

Background:

• Lowe syndrome and Dent disease are X-linked disorders caused by mutations in the inositol 5-phosphatase OCRL.
• OCRL interacts with the endocytic adaptor APPL1, linking it to cellular networks relevant to disease phenotypes.

Purpose of the Study:

• To investigate the role of APPL1 binding in OCRL localization to the endocytic pathway.
• To determine if disease-causing OCRL mutations affect its interaction with APPL1.

Main Methods:

• Analysis of OCRL interactions with APPL1 and other endocytic pathway components.
• Assessment of OCRL localization in cells expressing disease-associated OCRL missense mutations.
• Investigation of OCRL recruitment to endosomes using Rab5 activation.

Main Results:

• Binding to APPL1 is the sole OCRL interaction disrupted by all tested disease-causing missense mutations in the ASH-RhoGAP domains.
• APPL1 and Rab5 independently mediate OCRL recruitment to enlarged endosomes.
• Disruption of the OCRL-APPL1 interaction by mutations may impair OCRL function.

Conclusions:

• APPL1 binding is essential for targeting OCRL to specific cellular locations within the endocytic pathway.
• Impairment of the OCRL-APPL1 interaction due to mutations is a potential mechanism underlying Lowe syndrome and Dent disease.