OCRL

At least 20 mutations in the OCRL gene have been found to cause Dent disease 2. This form of Dent disease is characterized by chronic kidney problems; some affected individuals also have mild intellectual disability, weak muscle tone (hypotonia), and clouding of the lens of the eyes (cataract) that does not impair vision. Some researchers consider Dent disease 2 to be a mild variant of Lowe syndrome, which is discussed below.

The OCRL gene mutations that cause Dent disease 2 reduce or eliminate the function of the OCRL enzyme. These changes impair the transport of certain molecules and regulation of the actin cytoskeleton. They may also affect cell signaling by altering the structure or function of cilia. Disruption of these important cell activities likely impairs kidney function, leading to excess protein in the urine (proteinuria), kidney stones, and ultimately kidney failure. It is unknown how loss of the OCRL enzyme contributes to the other signs and symptoms of this condition.

Because the OCRL enzyme is present throughout the body, it is unclear why Dent disease 2 primarily affects the kidneys and, to a lesser extent, the brain, eyes, and other tissues. It is possible that other enzymes may be able to compensate for the defective OCRL enzyme in unaffected tissues.

More than 120 mutations in the OCRL gene have been identified in individuals with Lowe syndrome, a condition that affects the eyes, brain, and kidneys. Some of these mutations prevent the production of any OCRL enzyme. Other mutations reduce or eliminate the activity of the enzyme or prevent it from interacting with other proteins within the cell. Researchers believe that the effects of these genetic changes are similar to those of the mutations that cause Dent disease 2: the mutations likely alter the transport of molecules within cells, regulation of the actin cytoskeleton, and the structure and function of cilia. It is unknown why some OCRL gene mutations cause Lowe syndrome and others cause Dent disease 2.

Because the OCRL enzyme is present throughout the body, it is unclear why Lowe syndrome primarily affects the kidney, brain, and eyes. As with Dent disease 2, it is possible that other enzymes may be able to compensate for the defective OCRL enzyme in unaffected tissues.