Protein Trafficking Trouble Links Lowe Syndrome Symptoms in Brain and Kidney

New Haven, Conn. — Yale researchers have provided new insight into how mutations in a single gene may cause mental retardation and kidney problems in Lowe syndrome, a rare genetic condition that affects only boys.

Lowe syndrome causes cataracts, mental retardation, and a kidney dysfunction in which small proteins and ions are lost in the urine, which may lead to bone deformation and stunted growth.

The syndrome is caused by mutations in a gene that encodes an enzyme known as OCRL. Although researchers understand OCRL’s biochemical properties, it has been unclear how gene mutations that affect this enzyme’s function might contribute to the symptoms of Lowe syndrome.

In a new study in Developmental Cell, senior author Pietro De Camilli, professor of cell biology and neurobiology, said that the kidney defects associated with Lowe syndrome suggested that kidney cells might be improperly regulating receptor proteins on their surfaces that control the exchange of certain molecules between the urine and the blood.

DeCamilli is co-director of the medical school’s interdisciplinary program in Cellular Neuroscience, Neurodegeneration and Repair, a member of the Kavli Institute for Neuroscience, and a Howard Hughes Medical Institute investigator.

Using fluorescent tags to localize OCRL in human and monkey cells, De Camilli and his colleagues observed that the protein concentrates at structures on the cell’s surface called clathrin coated pits. The receptor molecules concentrate at these sites, which then pinch off from the cell membrane to form spherical vesicles. These vesicles transport the receptors and other proteins to intracellular compartments known as endosomes. Endosomes sort the transported proteins, sending some back to the cell surface and targeting others for destruction.

The researchers showed that normally OCRL attaches itself to APPL1, a protein which is associated with newly formed endocytic vesicles and endosomes and which is part of a protein scaffold that controls endocytic traffic and signaling of receptors. However, mutations that cause Lowe syndrome abolish the association of OCRL with APPL1, and this disruption may affect kidney cells’ ability to reabsorb materials bound by some of their cell surface receptors. OCRL also interacts with APPL1 in brain cells, where APPL1 is involved in transporting a nerve growth factor receptor. De Camilli and his colleagues suggest that the cognitive deficits seen in Lowe syndrome may be partly caused when the mutated OCRL gene impairs intracellular traffic and signaling in the brain.

“Our next steps will be to provide further evidence for the functional relevance in the disease of the new properties of OCRL that we have identified,” said De Camilli. “We hope that these studies will help design therapeutic strategies for the treatment of Lowe syndrome patients.”

Co-authors included Kai Erdmann, Yuxin Mao, Heather McCrea, Roberto Zoncu, Sangyoon Lee, Summer Paradise, Jan Modregger, Daniel Biemesderfer, Derek Toomre.