SLC26A2

The SLC26A2 gene provides instructions for making a protein that transports charged molecules (ions), particularly sulfate ions, across cell membranes. This protein appears to be active in many of the body's tissues, including developing cartilage. Cartilage is a tough, flexible tissue that makes up much of the skeleton during early development. Most cartilage is later converted to bone, except for the cartilage that continues to cover and protect the ends of bones and is present in the nose and external ears.

Cartilage cells use sulfate ions transported by the SLC26A2 protein to build molecules called proteoglycans. These molecules, which each consist of several sugars attached to a protein, help give cartilage its rubbery, gel-like structure. Because sulfate ions are required to make proteoglycans, the transport activity of the SLC26A2 protein is essential for normal cartilage formation.

achondrogenesis - caused by mutations in the SLC26A2 gene

At least nine mutations in the SLC26A2 gene are responsible for achondrogenesis type 1B. These mutations prevent the SLC26A2 gene from producing any functional protein. One common mutation deletes the amino acid valine (one of the building blocks of proteins) at position 340 in the SLC26A2 protein. This genetic change is written as delV340. Another common mutation (written as Arg178Ter or R178X) replaces the amino acid arginine at position 178 with a signal that prematurely stops protein production.

Mutations that cause achondrogenesis type 1B prevent cartilage cells from taking up the necessary sulfate ions. Without enough sulfate, the cell is unable to produce normal proteoglycans. A lack of these important molecules severely disrupts the structure of cartilage, making it look coarse and spongelike under a microscope. Because much of the skeleton develops from cartilage before birth and in early childhood, SLC26A2 mutations prevent bones from developing and growing normally, causing the skeletal abnormalities seen in achondrogenesis type 1B.

atelosteogenesis type 2 - caused by mutations in the SLC26A2 gene

Several SLC26A2 mutations that cause atelosteogenesis type 2 have been identified. Affected individuals typically have a mutation in one copy of the gene that disrupts the normal structure of the SLC26A2 protein, and a mutation in the other copy of the gene that prevents it from producing any functional protein.

A common SLC26A2 mutation replaces the amino acid arginine with the amino acid tryptophan at position 279 in the protein (written as Arg279Trp or R279W). In the Finnish population, the most common mutation (usually written as IVS1+2T>C) interferes with the normal processing of the SLC26A2 protein. Another common mutation replaces the amino acid arginine at position 178 with a signal that prematurely stops protein production(written as Arg178Ter or R178X).

SLC26A2 mutations alter the structure and function of the SLC26A2 transporter protein, which disrupts the ability of cartilage cells to take up the necessary sulfate ions. The cell is then unable to produce normal proteoglycans, which affects the structure of cartilage and the normal formation and growth of bones.

diastrophic dysplasia - caused by mutations in the SLC26A2 gene

More than 20 SLC26A2 mutations have been identified in people with diastrophic dysplasia. Like atelosteogenesis type 2, people with diastrophic dysplasia usually have a mutation in one copy of the gene that disrupts the normal structure of the SLC26A2 protein and a mutation in the other copy of the gene that prevents it from producing any functional protein.

These and several other mutations disrupt the ability of cartilage cells to take up the necessary sulfate ions. Without enough sulfate, the cell is unable to produce normal proteoglycans. A lack of these essential molecules affects the structure of cartilage and the normal formation and growth of bones.

multiple epiphyseal dysplasia - caused by mutations in the SLC26A2 gene

Mutations that cause recessive multiple epiphyseal dysplasia typically replace one amino acid with another amino acid in a noncritical segment of the SLC26A2 protein. The most common mutation that causes recessive multiple epiphyseal dysplasia replaces the amino acid arginine with the amino acid tryptophan at position 279 in the protein (written as Arg279Trp or R279W). Another mutation that commonly causes this condition replaces the amino acid cysteine with the amino acid serine at position 653 in the SLC26A2 protein (written as Cys653Ser or C653S).

The SLC26A2 mutations responsible for recessive multiple epiphyseal dysplasia tend to have less serious effects than mutations that cause severe skeletal disorders such as achondrogenesis type 1B. As a result of these milder mutations, the SLC26A2 protein likely retains some of its function as a transporter of sulfate ions. Cartilage and bone formation are less severely affected, which may help explain the relatively mild signs and symptoms characteristic of recessive multiple epiphyseal dysplasia.