The Maat-Kievit-Brunner type of Ohdo syndrome is a rare condition characterized by intellectual disability and distinctive facial features. It has only been reported in males.

The intellectual disability associated with this condition varies from mild to severe, and the development of motor skills (such as sitting, standing, and walking) is delayed. Some affected individuals also have behavioral problems.

Distinctive facial features often seen in this condition include a narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), prominent cheeks, a broad nasal bridge, a nose with a rounded tip, a large space between the nose and upper lip (a long philtrum), and a narrow mouth. Some affected individuals also have widely set eyes (hypertelorism), an unusually small chin (micrognathia), and small and low-set ears. As people with the condition get older, these facial characteristics become more pronounced and the face becomes more triangular.

Other possible signs of this condition include dental problems, weak muscle tone (hypotonia), and hearing loss.

The Maat-Kievit-Brunner type of Ohdo syndrome results from mutations in the MED12 gene. This gene provides instructions for making a protein that helps regulate gene activity; it is thought to play an essential role in development both before and after birth. The MED12 gene mutations that cause this condition alter the structure of the MED12 protein, impairing its ability to control gene activity. It is unclear how these changes lead to the particular cognitive and physical features of the Maat-Kievit-Brunner type of Ohdo syndrome.

Normal Function

The MED12 gene provides instructions for making a protein called mediator complex subunit 12. As its name suggests, this protein forms one part (subunit) of the mediator complex, which is a group of about 25 proteins that work together to regulate gene activity. The mediator complex physically links transcription factors, which are proteins that influence whether genes are turned on or off, with an enzyme called RNA polymerase II. Once transcription factors are attached, this enzyme initiates gene transcription, the process by which information stored in a gene's DNA is used to build proteins.

Researchers believe that the MED12 protein is involved in many aspects of early development, including the development of nerve cells (neurons) in the brain. The MED12 protein is part of several chemical signaling pathways within cells. These pathways help direct a broad range of cellular activities, such as cell growth, cell movement (migration), and the process by which cells mature to carry out specific functions (differentiation).

Health Conditions Related to Genetic Changes

FG syndrome

At least two mutations in the MED12 gene have been found to cause FG syndrome, which is characterized by intellectual disability, behavioral problems, and physical abnormalities including weak muscle tone (hypotonia) and obstruction of the anal opening (imperforate anus).

The mutations that cause FG syndrome each change a single protein building block (amino acid) in the MED12 protein. One mutation replaces the amino acid arginine with the amino acid tryptophan at protein position 961 (written as Arg961Trp or R961W). The other replaces the amino acid glycine with the amino acid glutamic acid at protein position 958 (written as Gly958Glu or G958E). These mutations alter the structure of the MED12 protein, which likely disrupts its ability to regulate gene activity during development. However, it is unclear how the genetic changes lead to intellectual disability and the other features of FG syndrome.

Lujan syndrome

At least one mutation in the MED12 gene causes Lujan syndrome, a disorder characterized by intellectual disability, behavioral problems, and physical features including tall stature and a long, narrow face. This mutation is different than the genetic changes associated with FG syndrome (described above); the Lujan syndrome mutation replaces the amino acid asparagine with the amino acid serine at position 1007 of the MED12 protein (written as Asn1007Ser or N1007S). The mutation alters the structure of the MED12 protein and likely disrupts its ability to regulate gene activity, but it is not known how these changes affect development and lead to the specific features of Lujan syndrome.

Ohdo syndrome, Maat-Kievit-Brunner type

At least three MED12 gene mutations have been found to cause the Maat-Kievit-Brunner type of Ohdo syndrome, which is a rare condition characterized by intellectual disability and distinctive facial features. The mutations that cause this disorder change single amino acids in the MED12 gene, although they are not the same genetic changes that cause FG syndrome or Lujan syndrome (described above). The mutations that result in the Maat-Kievit-Brunner type of Ohdo syndrome change the structure of the MED12 gene, impairing its ability to control gene activity. It is unclear how these changes lead to the particular cognitive and physical features of the disorder.

Prostate cancer

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Tumors

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are known as somatic mutations, are not inherited. Somatic mutations in the MED12 gene have been found in several types of tumors, both noncancerous and cancerous.

Somatic MED12 gene mutations are present in most uterine leiomyomas, which are noncancerous growths also known as uterine fibroids. Uterine leiomyomas are common in adult women. These growths can cause pelvic pain and abnormal bleeding, and, in some cases, lead to an inability to have biological children (infertility). Somatic MED12 gene mutations have also been identified in some cancerous uterine tumors, including leiomyosarcomas and smooth muscle tumors of uncertain malignant potential (STUMP), and in some prostate and colorectal cancers.

Studies suggest that somatic MED12 gene mutations alter the function of the MED12 protein, which likely disrupts normal cell signaling and impairs regulation of cell growth and other cell functions. As a result, certain cells may become able to divide in an uncontrolled way, leading to the growth of a tumor.

Other Names for This Gene

• CAGH45
• HOPA
• KIAA0192
• MED12_HUMAN
• mediator of RNA polymerase II transcription, subunit 12 homolog
• OKS
• OPA-containing protein
• OPA1
• thyroid hormone receptor-associated protein, 230 kDa subunit
• TNRC11
• TRAP230

Genomic Location

This condition is inherited in an X-linked recessive pattern. The MED12 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder.

Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. Females with only one altered copy of the gene in each cell are called carriers. They do not usually experience health problems related to the condition, but they can pass the mutation to their children. Sons who inherit the altered gene will have the condition, while daughters who inherit the altered gene will be carriers.

A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

The Maat-Kievit-Brunner type of Ohdo syndrome is a very rare condition, with only a few affected individuals reported in the medical literature.