Gene Associated With Multinodular Goiter: SLC26A4 = Pendred syndrome gene (Pendrin)

a.    The official name of the SLC26A4 gene

      The official name of this gene is “solute carrier family 26, member 4.” SLC26A4 is the gene's official symbol. The SLC26A4 gene is also known by other names.

b.    The normal function of the SLC26A4 gene

       The SLC26A4 gene provides instructions for making a protein called pendrin. This protein transports negatively charged particles (ions), including chloride, iodide, and bicarbonate, across cell membranes. Pendrin is present in the kidneys, inner ear, and thyroid. The thyroid is a butterfly-shaped tissue at the base of the neck that releases hormones to help regulate growth and the rate of chemical reactions in the body (metabolism).

       Although the function of pendrin is

not fully understood, researchers have suggested particular roles for pendrin in various tissues. In the thyroid, pendrin probably transports iodide ions out of cells. The attachment of iodide ions to a protein called thyroglobulin is an important step in the production of thyroid hormones. In the inner ear, pendrin likely helps control the proper balance of charged particles such as chloride and bicarbonate ions. Maintaining the correct level of these ions is critical for the hearing process and for determining the amount of fluid that bathes the inner ear. The fluid level appears to be particularly important during development of the inner ear, and it may influence the shape of the bony structures such as the cochlea and vestibular aqueduct. The cochlea is a snail-shaped structure that helps process sound. The vestibular aqueduct is a bony canal that connects the inner ear with the brain cavity.

c.    The SLC26A4 gene share characteristics with other genes

       The SLC26A4 gene belongs to a family of genes called SLC (solute carriers).  A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other.

d.   The SLC26A4 gene related to health conditions

Nonsyndromic deafness - caused by mutations in the SLC26A4 gene

       SLC26A4 mutations are associated with a form of nonsyndromic deafness (hearing loss without related signs and symptoms affecting other parts of the body) called DFNB4. People with DFNB4 deafness usually have an enlarged vestibular aqueduct.

      It can be difficult to distinguish DFNB4 from a condition called Pendred syndrome. In addition to hearing loss and an enlarged vestibular aqueduct, people with Pendred syndrome often have an enlarged thyroid gland (goiter) and a malformed cochlea. Both conditions are caused by mutations in the SLC26A4 gene, and almost all of the mutations associated with Pendred syndrome have also been found to cause DFNB4. These two conditions are considered part of a spectrum of hearing loss with or without other features.

       SLC26A4 mutations likely impair the activity of pendrin, which upsets the balance of ions and alters the levels of fluid in the inner ear. These changes presumably disrupt the development of structures in the inner ear and lead to hearing loss.

Pendred syndrome - caused by mutations in the SLC26A4 gene

       Researchers have identified more than 60 mutations in the SLC26A4 gene in people with Pendred syndrome. Some of these mutations change single protein building blocks (amino acids) used to make pendrin. Certain mutations occur more frequently in particular populations. For example, an SLC26A4 mutation common in the Japanese population replaces the amino acid histidine with the amino acid arginine at position 723 in the pendrin protein (written as His723Arg). Among Northern Europeans, common mutations in the SLC26A4 gene replace the amino acid threonine with the amino acid proline at protein position 416 (Thr416Pro) or replace the amino acid leucine with proline at position 236 (Leu236Pro). Other types of mutations alter the SLC26A4 gene by deleting or adding a small amount of DNA. These deletions and additions probably create a premature stop signal in the instructions for making pendrin. As a result, an abnormally small protein is made.

      Mutations in the SLC26A4 gene likely impair pendrin activity, disrupting ion transport. In the thyroid, disrupted transport prevents iodide ions from binding effectively to thyroglobulin. The thyroid tissue may enlarge to compensate for the perceived lack of iodine. In the inner ear, impaired pendrin activity probably upsets the balance of ions and alters the levels of fluid. These changes presumably disrupt the development of structures in the inner ear and lead to hearing loss.

e.    The SLC26A4 gene located

Cytogenetic Location: 7q31. Molecular Location on chromosome 7: base pairs 107,301,079 to 107,358,253. The SLC26A4 gene is located on the long (q) arm of chromosome 7 at position 31. More precisely, the SLC26A4 gene is located from base pair 107,301,079 to base pair 107,358,253 on chromosome 7.