CUL3-related neurodevelopmental disorder is a condition that affects neurological and physical development. Children with CUL3-related neurodevelopmental disorder may have intellectual disability or specific learning disorders. They may also experience delayed development of speech and motor skills, such as sitting and walking. Some individuals with this condition may have autism spectrum disorder, a developmental condition that affects communication and social skills.

Movement abnormalities can also occur in people with CUL3-related neurodevelopmental disorder. Affected individuals may have weak muscle tone (hypotonia) in childhood. In adulthood, they may develop involuntary muscle tensing (dystonia), rhythmic shaking (tremor), or other uncontrolled movements (spasms).

People with CUL3-related neurodevelopmental disorder can have distinctive facial features, including a long, triangular-shaped face; a large forehead; a large, rounded nose; small ears; deep-set eyes; or a pointed chin. Some affected individuals have a larger than normal head (macrocephaly).

Many people with CUL3-related neurodevelopmental disorder have hand and foot abnormalities. Hand abnormalities can include small pinky (fifth) fingers that curve inward (clinodactyly), narrow thumbs, underdevelopment of the muscle at the base of the thumb (thenar hypoplasia), or a single crease across the palm of the hand. Foot abnormalities can include high arches of the feet (pes cavus); bunions; fusion of the skin between some toes (cutaneous syndactyly); or joint deformities (contractures) in the ankles, feet, or toes. A few individuals with CUL3-related neurodevelopmental disorder have an abnormally curved lower back (lordosis) or a spine that curves to the side (scoliosis).

Some affected infants have a backflow of stomach acids into the esophagus (gastroesophageal reflux disease or GERD), which tends to go away after childhood. Rarely, recurrent seizures (epilepsy), congenital heart abnormalities, or genitourinary abnormalities occur in people with CUL3-related neurodevelopmental disorder.

CUL3-related neurodevelopmental disorder is caused by variants (also called mutations) in the CUL3 gene. This gene provides instructions for making a protein called cullin-3. The cullin-3 protein plays a role in the ubiquitin-proteasome system, which breaks down (degrades) unwanted proteins inside cells.

The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. By breaking down proteins at the right time, this system regulates the timing of critical cell activities, such as cell growth and division.

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.

Normal Function

The CUL3 gene provides instructions for making a protein called cullin-3. This protein plays a role in the ubiquitin-proteasome system, which breaks down (degrades) unwanted proteins inside cells.

The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. Cullin-3 is a core piece of a complex known as an E3 ubiquitin ligase. E3 ubiquitin ligases tag proteins with molecules called ubiquitin. Ubiquitin signals specialized cell structures known as proteasomes to attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system also regulates several critical cell activities by controlling the amounts of proteins involved in them.

E3 ubiquitin ligases that contain cullin-3 tag many proteins that perform a variety of functions, such as cell growth and division. These ligases also tag blood pressure-related proteins called WNK1 and WNK4, which are produced from the WNK1 and WNK4 genes. By regulating the amount of WNK1 and WNK4 available, cullin-3 plays a role in blood pressure control.

Health Conditions Related to Genetic Changes

CUL3-related neurodevelopmental disorder

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.

Pseudohypoaldosteronism type 2

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.

Other Names for This Gene

• CUL-3
• cullin-3 isoform 1
• cullin-3 isoform 2
• cullin-3 isoform 3
• PHA2E

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) variants in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These affected individuals have no history of the disorder in their family.

CUL3-related neurodevelopmental disorder is a rare disorder, though its exact prevalence is unknown.