MID1

The MID1 gene is part of a group of genes called the TRIM family. Proteins produced from this large family of genes are involved in many cellular activities. Primarily, TRIM proteins play a role in the cell machinery that breaks down (degrades) unwanted proteins by tagging them with molecules called ubiquitin. Ubiquitin serves as a signal to move these unwanted proteins into specialized structures known as proteasomes, where the proteins are degraded.

The MID1 gene provides instructions for making a protein called midin or midline-1. This protein helps regulate the function of microtubules, which are rigid, hollow fibers that make up the cell's structural framework (the cytoskeleton). Microtubules help cells maintain their shape, assist in the process of cell division, and are essential for the transport of materials within cells. As part of its protein degrading function, midin is responsible for breaking down an enzyme called protein phosphatase 2A (PP2A). This enzyme activates a number of microtubule-associated proteins.

Opitz G/BBB syndrome - caused by mutations in the MID1 gene

More than 40 mutations in the MID1 gene have been identified in people with X-linked Opitz G/BBB syndrome. The majority of these mutations change a single protein building block (amino acid) in the midin protein. Other mutations include deletions or insertions of more than one amino acid and splice site mutations, which cause the protein to be pieced together incorrectly. All these mutations cause the non-functioning midin to be unable to attach (bind) to microtubules and break down PP2A. As a result, PP2A builds up in cells. An excess of this protein abnormally alters the functions of microtubule-associated proteins, which in turn can disrupt the normal function of microtubules. It is unclear how these changes interfere with normal development and cause the birth defects associated with Opitz G/BBB syndrome. Researchers speculate that the nonfunctional midin affects how the cells divide and associate along the midline of the body during development, resulting in many of the abnormalities seen in Opitz G/BBB syndrome.