3-M syndrome is a disorder that causes skeletal abnormalities including short stature (dwarfism) and unusual facial features. The name of this condition comes from the initials of three researchers who first identified it: Miller, McKusick, and Malvaux.

Individuals with 3-M syndrome grow extremely slowly before birth, and this slow growth continues throughout childhood and adolescence. They have low birth weight and length and remain much smaller than others in their family, growing to an adult height of approximately 4 feet to 4 feet 6 inches (120 centimeters to 130 centimeters). In some affected individuals, the head is normal-sized but looks disproportionately large in comparison with the body. In other people with this disorder, the head has an unusually long and narrow shape (dolichocephaly). Intelligence is unaffected by 3-M syndrome, and life expectancy is generally normal.

In addition to short stature, people with 3-M syndrome have a triangle-shaped face with a broad, prominent forehead (frontal bossing) and a pointed chin; the middle of the face is less prominent (hypoplastic midface). Other common features include large ears, full eyebrows, an upturned nose with a fleshy tip, a long area between the nose and mouth (philtrum), a prominent mouth, and full lips.

Other skeletal abnormalities that often occur in this disorder include a short, broad neck and chest; prominent shoulder blades; and shoulders that slope less than usual (square shoulders). Affected individuals may have abnormal spinal curvature such as a rounded upper back that also curves to the side (kyphoscoliosis) or exaggerated curvature of the lower back (hyperlordosis). People with 3-M syndrome can also have unusual curving of the fingers (clinodactyly), short fifth (pinky) fingers, prominent heels, and loose joints. Additional skeletal abnormalities, such as unusually slender long bones in the arms and legs; tall, narrow spinal bones (vertebrae); or slightly delayed bone age may be apparent in x-ray images.

A variant of 3-M syndrome called Yakut short stature syndrome has been identified in the isolated Yakut population in the Russian province of Siberia. In addition to having most of the physical features characteristic of 3-M syndrome, people with this form of the disorder are often born with breathing problems that can be life-threatening in infancy.

Mutations in the CUL7 gene cause 3-M syndrome in more than three-quarters of affected individuals, including those in the Yakut population. Mutations in the OBSL1 gene cause about 16 percent of cases of this disorder. Mutations in other genes, some of which have not been identified, account for the remaining cases.

The CUL7 gene provides instructions for making a protein called cullin-7. The cullin-7 protein plays a role in the cell machinery that breaks down (degrades) unwanted proteins, called the ubiquitin-proteasome system. Specifically, cullin-7 helps assemble a complex called an E3 ubiquitin ligase, which tags the unneeded proteins for degradation. The protein produced from the OBSL1 gene is thought to help maintain normal levels of cullin-7.

The ubiquitin-proteasome system helps regulate the level of proteins involved in several critical cell activities such as the timing of cell division and growth. In particular, the proteins produced from the genes associated with 3-M syndrome are thought to help regulate proteins involved in the body's response to growth hormones, although their specific role in this process is unknown.

Mutations in the CUL7 or OBSL1 gene prevent the cullin-7 protein from bringing together the components of the E3 ubiquitin ligase complex, interfering with the process of tagging unneeded proteins for degradation. The body's response to growth hormones may be impaired as a result. However, the specific relationship between CUL7 and OBSL1 gene mutations and the signs and symptoms of 3-M syndrome are unknown.

Normal Function

The CUL7 gene provides instructions for making a protein called cullin-7. This protein plays a role in the ubiquitin-proteasome system, which is the cell machinery that breaks down (degrades) unwanted proteins.

Cullin-7 helps assemble a complex known as an E3 ubiquitin ligase. This complex tags damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth. In particular, cullin-7 is thought to help regulate proteins involved in the body's response to growth hormones, although its specific role in this process is unknown.

Health Conditions Related to Genetic Changes

3-M syndrome

At least 73 mutations in the CUL7 gene have been identified in people with 3-M syndrome, a disorder that causes skeletal anomalies including short stature (dwarfism) and unusual facial features. Most of these mutations substitute one protein building block (amino acid) for another amino acid in the cullin-7 protein or result in a cullin-7 protein that is abnormally short and nonfunctional.

Individuals in the Yakut population of the Russian province of Siberia with a variant of 3-M syndrome all have a particular mutation in both copies of the CUL7 gene in each cell. This mutation replaces the amino acid glutamine with a premature stop signal in the instructions for making the cullin-7 protein (written as Gln1553Ter or Q1553X), leading to production of an abnormally short protein.

Mutations in the CUL7 gene, including the Gln1553Ter mutation, prevent the cullin-7 protein from bringing together the components of the E3 ubiquitin ligase complex, interfering with the process of tagging unneeded proteins for degradation. The body's response to growth hormones may be impaired as a result. However, the specific relationship between CUL7 gene mutations and the signs and symptoms of 3-M syndrome are unknown.

Other Names for This Gene

• CUL7_HUMAN
• dJ20C7.5
• KIAA0076

Genomic Location

Normal Function

The OBSL1 gene provides instructions for making a protein that is thought to help maintain normal levels of another protein called cullin-7, which is produced from the CUL7 gene. The cullin-7 protein plays a role in the ubiquitin-proteasome system, which is the cell machinery that breaks down (degrades) unwanted proteins.

Cullin-7 helps assemble a complex known as an E3 ubiquitin ligase. This complex tags damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to specialized cell structures known as proteasomes, which attach (bind) to the tagged proteins and degrade them. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the level of proteins involved in several critical cell activities such as the timing of cell division and growth. In particular, the OBSL1 protein and cullin-7 are thought to help regulate proteins involved in the body's response to growth hormones, although their specific role in this process is unknown.

Health Conditions Related to Genetic Changes

3-M syndrome

At least 29 mutations in the OBSL1 gene have been identified in people with 3-M syndrome, a disorder that causes skeletal abnormalities including short stature (dwarfism) and unusual facial features. Most of these mutations substitute one protein building block (amino acid) for another amino acid in the OBSL1 protein or result in an OBSL1 protein that is abnormally short and nonfunctional.

Mutations in the OBSL1 gene likely lead to reduced cullin-7 protein levels, preventing cullin-7 from bringing together the components of the E3 ubiquitin ligase complex and interfering with the process of tagging unneeded proteins for degradation. The body's response to growth hormones may be impaired as a result. However, the specific relationship between OBSL1 gene mutations and the signs and symptoms of 3-M syndrome are unknown.

Other Names for This Gene

• KIAA0657
• obscurin-like protein 1 isoform 1 precursor
• obscurin-like protein 1 isoform 2 precursor
• obscurin-like protein 1 isoform 3 precursor

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

The prevalence of 3-M syndrome is unknown. About 100 individuals worldwide with this disorder have been described in the medical literature.