Saul-Wilson syndrome is characterized by short stature (dwarfism) and other skeletal abnormalities. The growth problems in Saul-Wilson syndrome are called primordial, which means they begin before birth; affected individuals show slow prenatal growth (intrauterine growth retardation). After birth, affected individuals continue to grow at a very slow rate, with the average adult height being 3 feet, 6 inches (107 centimeters).

Individuals with Saul-Wilson syndrome have distinctive facial features that often include a prominent forehead, sparse scalp hair and eyebrows, prominent scalp veins, a narrow nasal bridge, a beaked nose, a wide area separating the nostrils (broad columella), a thin upper lip, and a small lower jaw (micrognathia). This combination of facial features can give affected individuals an appearance of premature aging, particularly in infancy, that is sometimes described as progeroid.

Additional skeletal abnormalities in Saul-Wilson syndrome include abnormalities in the structure of the long bones, short fingers and toes, an inward- and downward-turning foot (clubfoot), an abnormality of the hip joint that causes a decreased angle between the head and shaft of the upper leg bones (coxa vara), or flattened bones of the spine (platyspondyly) and other spinal abnormalities. Some affected individuals have bones that are unusually fragile, resulting in bone fractures that occur with little or no trauma. Adults with Saul-Wilson syndrome may experience joint pain (osteoarthritis) due to breakdown (degeneration) of the joints.

Children with Saul-Wilson syndrome often have hearing loss, clouding of the lenses of the eyes (cataracts), or a blue tint to the whites of the eyes (blue sclerae). They may also have retinitis pigmentosa, in which breakdown of the light-sensitive layer (retina) at the back of the eye can cause vision loss. Individuals with Saul-Wilson syndrome may have early delay of speech and motor development, but they usually have normal intelligence.

In Saul-Wilson syndrome, levels of white blood cells can vary from normal to low (intermittent neutropenia). Neutropenia makes it more difficult for the body to fight off foreign invaders such as bacteria and viruses, and may contribute to recurrent respiratory infections that occur in childhood in some individuals with Saul-Wilson syndrome.

Saul-Wilson syndrome is caused by mutations in the COG4 gene. This gene provides instructions for making one piece of a group of proteins known as the conserved oligomeric Golgi (COG) complex. This complex functions in the Golgi apparatus, which is a cellular structure in which newly produced proteins are modified so they can carry out their functions. The COG complex plays an important role in the transport of proteins from the Golgi apparatus to another cellular structure called the endoplasmic reticulum. The endoplasmic reticulum processes proteins and helps move them to other structures in the cell. Transporting proteins from the Golgi apparatus to the endoplasmic reticulum (known as retrograde transport) is important for recycling proteins and relocating misplaced proteins.

The COG4 gene mutations that cause Saul-Wilson syndrome result in production of an abnormal COG4 protein. Although the protein is altered, it is still able to be a part of the COG complex. When the abnormal COG4 protein is part of the COG complex, the transport of proteins between the Golgi apparatus and the endoplasmic reticulum is increased. It is unclear how this change in retrograde transport impairs bone growth and leads to the signs and symptoms of Saul-Wilson syndrome.

Normal Function

The COG4 gene provides instructions for making a protein called component of oligomeric Golgi complex 4 (COG4). As its name suggests, COG4 is one piece of a group of proteins known as the conserved oligomeric Golgi (COG) complex. This complex is important for maintaining normal functions in the Golgi apparatus, which is a cell structure in which newly produced proteins are modified so they can carry out their functions. An example of a protein modification process that occurs in the Golgi apparatus is glycosylation, by which sugar molecules (oligosaccharides) are attached to proteins and fats. Glycosylation modifies proteins so they can perform a wider variety of functions.

The COG complex plays an important role in a process called retrograde transport, through which proteins are moved from the Golgi apparatus to another cellular structure called the endoplasmic reticulum. Among its many functions, the endoplasmic reticulum folds and modifies newly formed proteins so they have the correct 3-dimensional shape. This transport pathway is called retrograde because it is in reverse order of the usual process for newly produced proteins. New proteins undergo initial processing in the endoplasmic reticulum then move to the Golgi apparatus for further modification before being released from the cell (secreted). Retrograde transport is important for sending unneeded proteins to the endoplasmic reticulum to get recycled and for relocating misplaced proteins within the cell.

For retrograde transport, proteins first must be incorporated into sac-like structures called vesicles that get attached to the Golgi apparatus membrane. The COG complex controls the attachment (tethering) of the vesicles to the Golgi membrane in preparation for transport. Once the proteins are incorporated, the vesicles detach and carry the proteins to the endoplasmic reticulum.

Health Conditions Related to Genetic Changes

Saul-Wilson syndrome

At least two mutations in the COG4 gene have been found to cause Saul-Wilson syndrome, a condition characterized by short stature (dwarfism) and other skeletal abnormalities. The mutations change single DNA building blocks (nucleotides) in the COG4 gene. These two nucleotide changes result in the same alteration in the COG4 protein. The protein building block (amino acid) glycine is switched to the amino acid arginine at position 516 in the protein (written as Gly516Arg or G516R).

The amino acid change in the COG4 protein alters its structure, but the abnormal protein is still able to be a part of the COG complex. When the abnormal COG4 protein is incorporated into the COG complex, retrograde transport of proteins between the Golgi apparatus and the endoplasmic reticulum is increased. Because the COG4 gene mutations enhance the COG complex's function, they are described as "gain-of-function." It is unclear how increased retrograde transport impairs bone growth and leads to the signs and symptoms of Saul-Wilson syndrome.

Other disorders

Mutations in the COG4 gene have also been found to cause a condition called COG4-congenital disorder of glycosylation (COG4-CDG). This condition often leads to developmental delay, intellectual disability, seizures, and an unusually small head size (microcephaly). Mutations in the COG4 gene that cause COG4-CDG reduce the amount of COG4 protein or eliminate it completely, which likely impairs COG complex formation and its role in maintaining the normal function of the Golgi apparatus. A dysfunctional Golgi apparatus results in abnormal protein glycosylation, which can affect multiple body systems, leading to the signs and symptoms of COG4-CDG.

Other Names for This Gene

• COD1
• COD1, S. CEREVISIAE, HOMOLOG OF
• COG4 gene

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) mutations 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 cases occur in people with no history of the disorder in their family.

Saul-Wilson syndrome is a very rare disorder. At least 16 affected individuals have been reported in the scientific literature.