On this page
SLC26A4
solute carrier family 26 member 4
The SLC26A4 gene provides instructions for the pendrin protein, crucial for ion transport in the inner ear and thyroid gland, and is associated with conditions like Pendred syndrome. The SLC26A4 gene encodes the pendrin protein, a transporter of negatively charged ions such as chloride, iodide, and bicarbonate across cell membranes.
SLC26A4 is located on the long (q) arm of chromosome 7, at band 7q22.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 7 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The SLC26A4 gene, also known as PDS, contains the genetic instructions for producing a protein called pendrin. This protein functions as an ion transporter, moving negatively charged particles like chloride, iodide, and bicarbonate across cell membranes. Pendrin is particularly important in the inner ear and the thyroid gland, where it contributes to crucial physiological processes.
Disruptions to the SLC26A4 gene are associated with autosomal recessive inherited conditions, primarily affecting hearing and thyroid function, such as Pendred syndrome and DFNB4/Enlarged vestibular aqueduct.
What the gene does
The pendrin protein, encoded by the SLC26A4 gene, primarily facilitates the transport of various negatively charged ions, including chloride, iodide, and bicarbonate, across cellular membranes. In the thyroid gland, pendrin is thought to move iodide ions out of specific cells, a process vital for the normal synthesis of thyroid hormones. The thyroid gland is a key endocrine organ that regulates metabolism and growth.
Within the inner ear, pendrin is believed to be crucial for maintaining the precise balance of ions, including chloride and bicarbonate. This proper ion balance is especially important during the development of the inner ear structures. It can influence the formation of bony components like the cochlea, which processes sound, and the vestibular aqueduct, which connects the inner ear to the skull. Pendrin is also found in other tissues, such as the kidneys, liver, and airway lining, though its specific roles there are still under investigation.
Video: Genetics 101
Chromosome location
The SLC26A4 gene is situated on the long arm of chromosome 7 at position 7q22.3. This specific location indicates its position within the human genome.
Protein structure
The SLC26A4 gene produces a protein called pendrin, which is 780 amino acids long. The protein features a significant STAS (Domain) located between amino acids 535 and 729. This domain is believed to play a role in regulating the activity of anion transporters.
Key variants
Genetic variations within the SLC26A4 gene can alter the structure and function of the pendrin protein. More than 150 different pathogenic variants in the SLC26A4 gene have been identified, including those that lead to changes in single amino acid building blocks of the protein. These changes can impair the protein's ability to transport ions effectively, leading to the clinical manifestations of associated conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1149+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Rare genetic deafness |
c.1150G>C | p.Glu384Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Deafness |
c.1545T>A | p.Phe515Leu | Pathogenic/Likely pathogenic | ★★☆☆ | Pendred syndrome |
c.1553G>A | p.Trp518Ter | Pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 4 |
c.1708-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pendred syndrome |
c.2235+2T>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 4 |
c.327del | p.Ala110fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pendred syndrome |
c.384del | p.Phe128fs | Pathogenic/Likely pathogenic | ★★☆☆ | SLC26A4-related disorder |
c.556_562del | p.Val186fs | Pathogenic/Likely pathogenic | ★★☆☆ | Pendred syndrome |
c.991_1001+7delinsCCCCA | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pendred syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the SLC26A4 gene are primarily associated with inherited conditions affecting hearing and thyroid function. These include Pendred syndrome, which is characterised by hearing loss, inner ear abnormalities such as an enlarged vestibular aqueduct, and often an enlarged thyroid gland (goitre). The gene is also linked to DFNB4/Enlarged vestibular aqueduct, which primarily involves hearing loss and inner ear malformations without the thyroid involvement seen in Pendred syndrome.
Inheritance pattern
Conditions caused by pathogenic SLC26A4 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SLC26A4 is recognised within the UK's NHS Genomic Medicine Service pathways. It is listed on PanelApp for its association with Monogenic hearing loss (R67), Deafness and congenital structural abnormalities, and Congenital hypothyroidism (R145), all classified as 'green' indicating high evidence for clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the SLC26A4 gene?
The SLC26A4 gene provides instructions for making the pendrin protein, which transports negatively charged ions like chloride, iodide, and bicarbonate. This transport is crucial for maintaining ion balance in the inner ear and for the production of thyroid hormones.
What conditions are associated with SLC26A4 variants?
Pathogenic variants in the SLC26A4 gene are primarily associated with inherited conditions such as Pendred syndrome and DFNB4/Enlarged vestibular aqueduct. These conditions often involve hearing loss and abnormalities of the inner ear, with Pendred syndrome also typically including an enlarged thyroid gland.
How is SLC26A4 relevant to hearing?
In the inner ear, the pendrin protein helps regulate the balance of ions, which is vital for the proper development of inner ear structures like the cochlea and vestibular aqueduct. Disruptions to this balance due to SLC26A4 variants can lead to hearing impairment.
References
- Fang Y, Gu M, Wang C. GJB2 as Well as SLC26A4 Gene Mutations are Prominent Causes for Congenital Deafness. Cell biochemistry and biophysics. 2015. PMID: 25649612
- Tsukada K, Nishio SY, Hattori M. Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review. The Annals of otology, rhinology, and laryngology. 2015. PMID: 25999548
- Kühnen P, Turan S, Fröhler S. Identification of PENDRIN (SLC26A4) mutations in patients with congenital hypothyroidism and "apparent" thyroid dysgenesis. The Journal of clinical endocrinology and metabolism. 2014. PMID: 24248179
- Kopp P. Mutations in the Pendred Syndrome (PDS/SLC26A) gene: an increasingly complex phenotypic spectrum from goiter to thyroid hypoplasia. The Journal of clinical endocrinology and metabolism. 2014. PMID: 24384016
- Ito T, Choi BY, King KA. SLC26A4 genotypes and phenotypes associated with enlargement of the vestibular aqueduct. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2011. PMID: 22116369
- Dossena S, Rodighiero S, Vezzoli V. Functional characterization of wild-type and mutated pendrin (SLC26A4), the anion transporter involved in Pendred syndrome. Journal of molecular endocrinology. 2009. PMID: 19608655
- Albert S, Blons H, Jonard L. SLC26A4 gene is frequently involved in nonsyndromic hearing impairment with enlarged vestibular aqueduct in Caucasian populations. European journal of human genetics : EJHG. 2006. PMID: 16570074
- Scott DA, Wang R, Kreman TM. The Pendred syndrome gene encodes a chloride-iodide transport protein. Nature genetics. 1999. PMID: 10192399
- Li XC, Everett LA, Lalwani AK. A mutation in PDS causes non-syndromic recessive deafness. Nature genetics. 1998. PMID: 9500541