CUL3

CUL3 gene variants (also called mutations) can cause a condition called CUL3-related neurodevelopmental disorder. This condition affects neurological and physical development. 

The CUL3 gene variants that cause CUL3-related neurodevelopmental disorder can lead to the production of nonfunctional cullin-3 proteins, and in some cases, no cullin-3 protein production at all.  Without the normal amount of functioning cullin-3 proteins, the breakdown of unwanted proteins by the ubiquitin-proteasome system becomes impaired at key developmental stages. As a result, unnecessary proteins build up and interfere with the normal function of cells. Since cullin-3 is produced in nerve cells throughout the brain, it is likely that the protein's dysfunction damages nerve cells, causing many of the signs and symptoms of CUL3-related neurodevelopmental disorder.

Researchers suspect that each variant that causes CUL3-related neurodevelopmental disorder affects the tagging of specific proteins by the E3 ubiquitin ligase complex. So, each variant could interfere with the breakdown of proteins differently. This mechanism may explain the variety of signs and symptoms seen in individuals with CUL3-related neurodevelopmental disorder.

Specific variants in a particular region of the CUL3 gene can cause pseudohypoaldosteronism type 2 (PHA2), a condition characterized by high blood pressure (hypertension) and high levels of potassium in the blood (hyperkalemia). These variants lead to the production of an abnormally short cullin-3 protein that is missing a particular region. 

Studies show that this change alters the function of the E3 ubiquitin ligase complex. It impairs the breakdown of the WNK4 protein, although the exact mechanism is unclear. The resulting excess of WNK4 protein disrupts normal control of blood pressure, causing hypertension and other features of PHA2. While PHA2 and CUL3-related neurodevelopmental disorder share a genetic cause, the features of PHA2 do not overlap with the neurological or physical problems of CUL3-related neurodevelopmental disorder.

It is unknown if the breakdown of WNK1 is affected by the alterations to E3 ubiquitin ligase or whether WNK1 plays a role in cases of PHA2 caused by CUL3 gene variants.