MN1 C-terminal truncation (MCTT) syndrome is a condition characterized by intellectual disability, developmental delay, distinctive facial features, and brain abnormalities.

Most people with MCTT syndrome have mild to moderate intellectual disability. Many affected individuals are nonverbal, but some have speech limited to one or two words or communicate using sign language. Most children with this condition have delayed development of motor skills, such as crawling or walking, but are able to walk by age 2 or 3. However, they often need help with fine-motor skills, such as getting dressed or using a fork when eating.

Individuals with MCTT syndrome often have distinctive facial features that include a sunken appearance of the middle of the face (midface hypoplasia ); a high arch in the roof of the mouth (high-arched palate ); outside corners of the eyes that point downward (downslanting palpebral fissures); widely spaced eyes (hypertelorism ); shallow and bulging eyes (exophthalmos); a short, upturned nose; and small, low-set ears. Some affected individuals have dental abnormalities, such as cone-shaped (conical ), jagged, or crowded teeth. Rarely, people with MCTT syndrome have premature fusion of certain skull bones (craniosynostosis).

People with MCTT syndrome often have characteristic brain abnormalities. The surface of the brain normally has many ridges or folds, called gyri. A common brain abnormality in people with MCTT syndrome is called perisylvian polymicrogyria, in which an area of the brain called the perisylvian region develops too many gyri, and the folds are irregular and unusually small. Individuals with MCTT syndrome can also have a malformation of the part of the brain that coordinates movement (the cerebellum ). This malformation, called atypical rhombencephalosynapsis, is characterized by tissue loss in the central part of the cerebellum (known as the vermis) and fusion of the two sides of the cerebellum. These brain abnormalities likely contribute to the movement problems and intellectual disability that are common in MCTT syndrome.

Less common features of MCTT syndrome include hearing loss, seizures, abnormal curvature of the spine, and heart abnormalities.

MCTT syndrome is caused by mutations in the MN1gene. This gene provides instructions for making a protein whose function is unclear. Based on its interaction with other proteins, the MN1 protein is thought to play a role in regulating the activity of other genes, particularly those needed for the development of the skull and brain.

All MN1 gene mutations that cause MCTT syndrome occur near the end (terminal) portion of the gene. As a result, an abnormally short (truncated) protein is produced. These mutations are reflected in the condition name, MN1 C-terminal truncation syndrome.

Research shows that a shortened MN1 protein cannot interact with other proteins, leading to a buildup of the abnormal MN1 protein in the cell nucleus. It is likely that without the normal function of the MN1 protein, the activity of certain genes involved in the development of the skull and brain is unregulated, leading to the signs and symptoms of MCTT syndrome.

Normal Function

The MN1 gene provides instructions for making a protein whose function is unclear. The MN1 protein interacts with other proteins known as transcription factors. These proteins attach to specific areas of DNA and help control the activity of particular genes. Based on its interaction with transcription factors, the MN1 protein is thought to play a role in regulating the activity of other genes, particularly those that are needed for the development of the skull and brain.

Health Conditions Related to Genetic Changes

MN1 C-terminal truncation syndrome

At least 11 mutations in the MN1 gene have been found to cause MN1 C-terminal truncation (MCTT) syndrome. This condition is characterized by intellectual disability, developmental delay, distinctive facial features, and brain abnormalities.

All MN1 gene mutations that cause MCTT syndrome occur near the end (terminal) portion of the gene. As a result, an abnormally short (truncated) protein is produced. These mutations are reflected in the condition name, MN1 C-terminal truncation syndrome.

One mutation that has been found in multiple people with this condition replaces the protein building block (amino acid) arginine at position 1295 with a premature stop signal in the instructions for making the MN1 protein (written Arg1295Ter or R1295*). Like all mutations that cause MCTT syndrome, this mutation results in an abnormally short protein.

Research shows that shortened MN1 proteins are unable to interact with other proteins, and the abnormal proteins build up in the cell nucleus. It is likely that shortage of normal functioning MN1 prevents the regulation of many other genes, such as those involved in skull and brain development, resulting in the characteristic features of MCTT syndrome.

Other disorders

Certain mutations in the MN1 gene have been associated with hearing loss and speech problems without other symptoms of MCTT syndrome (described above). The mutations that cause these features occur in the front portion of the gene and result in the production of an abnormally short protein that gets quickly broken down. These mutations contrast with those that cause MCTT syndrome, which are at the end of the gene and result in buildup of the abnormal protein in the cell.

Some people with large deletions of DNA that include the MN1 gene have been found to have developmental delay, intellectual disabilities, and craniofacial abnormalities. While these features are similar to those of MCTT syndrome, the conditions are distinct.

In addition, increased activity (overexpression) of the MN1 gene typically indicates a poor outcome (prognosis) in people with cancers of blood-forming cells (leukemia). The genetic changes involved in this overexpression happens when a break occurs in the MN1 gene which brings it together with part of another gene on another chromosome, creating a fusion gene. These changes are somatic, which means that they occur only in the tumor cells and are not inherited. People with MCTT syndrome do not appear to have an increased risk of leukemia.

Other Names for This Gene

• MGCR
• MGCR1
• MGCR1-PEN

Genomic Location

The MN1 gene is found on chromosome 22.

MCTT syndrome 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 MN1 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.

The prevalence of MCTT syndrome is unknown, although it is thought to be a rare disorder. At least 25 affected individuals have been described in the scientific literature.