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SLC26A2
solute carrier family 26 member 2
The SLC26A2 gene provides instructions for a protein critical in transporting sulphate ions, which is essential for the healthy development of cartilage and bone. The SLC26A2 gene encodes a protein responsible for transporting sulphate ions across cell membranes.
SLC26A2 is located on the long (q) arm of chromosome 5, at band 5q32. Arm ratio per GRCh38 - banding schematic.
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Overview
The SLC26A2 gene, also known as solute carrier family 26 member 2, plays a crucial role in human development by producing a protein that facilitates the movement of charged molecules, specifically sulphate ions, across cell membranes. This protein is particularly active in developing cartilage, a flexible tissue that forms a significant part of the early skeleton. The correct function of the SLC26A2 protein is therefore fundamental for normal cartilage and bone development.
Mutations in this gene are linked to a spectrum of inherited conditions affecting cartilage and bone, typically inherited in an autosomal recessive manner. These conditions, often referred to as skeletal dysplasias, vary in severity but generally impact skeletal growth and structure.
What the gene does
The SLC26A2 gene provides the blueprint for a protein that acts as an ion transporter. Its primary function involves moving sulphate ions across cellular membranes, particularly within cells responsible for forming cartilage. Cartilage cells utilise these transported sulphate ions to construct proteoglycans, which are complex molecules made of proteins and sugars.
Proteoglycans are vital components of the extracellular matrix of cartilage, contributing to its rubbery, gel-like consistency and structural integrity. Since sulphate ions are indispensable for the synthesis of these proteoglycans, the sulphate transport activity of the SLC26A2 protein is directly involved in supporting normal cartilage formation and subsequent bone development. Disruptions to this transport mechanism can lead to structural defects in cartilage and bone.
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Chromosome location
The SLC26A2 gene is situated on chromosome 5, specifically at position 5q32. This gene provides instructions for a protein that is 739 amino acids in length. Its location on chromosome 5 means that genetic variations within this region can have significant impacts on the physiological processes it governs.
Protein structure
The SLC26A2 protein, comprising 739 amino acids, features a defined domain architecture critical for its function. An N-terminal Disordered region spans amino acids 1-27. Further along the protein, a STAS (Sulphate Transporter Anti-Sigma factor antagonist) Domain is located between amino acids 568-719. These domains are important for the protein's overall structure and its ability to transport sulphate ions effectively.
Key variants
Variants within the SLC26A2 gene can significantly impact its function, potentially leading to reduced or absent sulphate transport activity. These genetic changes are usually inherited in an autosomal recessive pattern, meaning an individual must inherit two altered copies of the gene (one from each parent) to develop a related condition. Over 20 different mutations in this gene have been identified across the spectrum of associated disorders.
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.1336A>T | p.Lys446Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
c.136_137insTT | p.Asp46fs | Pathogenic/Likely pathogenic | ★★☆☆ | Diastrophic dysplasia |
c.1796T>A | p.Leu599Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Atelosteogenesis type II |
c.1847del | p.Ala616fs | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
c.2065_2068delinsTC | p.Thr689fs | Pathogenic/Likely pathogenic | ★★☆☆ | SLC26A2-related skeletal dysplasia |
c.294G>A | p.Trp98Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
c.314del | p.Lys105fs | Pathogenic/Likely pathogenic | ★★☆☆ | SLC26A2-related skeletal dysplasia |
c.822del | p.Leu275fs | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
c.854C>A | p.Ser285Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
c.916_929dup | p.Cys311fs | Pathogenic/Likely pathogenic | ★★☆☆ | Achondrogenesis, type IB |
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 SLC26A2 gene are associated with a group of inherited skeletal dysplasias that affect cartilage and bone development. These conditions include diastrophic dysplasia, achondrogenesis type 1B (Parenti-Fraccaro type), atelosteogenesis type 2, and the recessive form of multiple epiphyseal dysplasia. The severity of these conditions can vary, ranging from severe, life-limiting forms to milder presentations, all stemming from impaired sulphate transport essential for cartilage formation.
Inheritance pattern
Conditions caused by pathogenic SLC26A2 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
The SLC26A2 gene is recognised within the UK's NHS Genomic Medicine Service, featuring on several national testing panels. It is listed on the Clefting, DDG2P, Foetal anomalies (R21), Limb disorders, Multiple Epiphyseal Dysplasia, and Skeletal dysplasia (R104) panels. This inclusion underscores its clinical significance in diagnosing a range of skeletal and developmental conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the SLC26A2 gene?
The SLC26A2 gene provides instructions for a protein that transports sulphate ions across cell membranes. This function is critical for the production of proteoglycans, which are essential components of healthy cartilage and bone development.
What conditions are associated with changes in the SLC26A2 gene?
Variants in the SLC26A2 gene are associated with a group of inherited skeletal dysplasias, including diastrophic dysplasia, achondrogenesis type 1B, atelosteogenesis type 2, and multiple epiphyseal dysplasia. These conditions primarily affect cartilage and bone development.
How are conditions related to SLC26A2 typically inherited?
Conditions linked to the SLC26A2 gene are generally inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to be affected by the condition.
References
- Alper SL, Sharma AK. The SLC26 gene family of anion transporters and channels. Molecular aspects of medicine. 2013. PMID: 23506885
- Maeda K, Miyamoto Y, Sawai H. A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia. American journal of medical genetics. Part A. 2006. PMID: 16642506
- Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Human mutation. 2001. PMID: 11241838
- Karniski LP. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype. Human molecular genetics. 2001. PMID: 11448940
- Haila S, Hästbacka J, Böhling T. SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 2001. PMID: 11457925
- Superti-Furga A, Neumann L, Riebel T. Recessively inherited multiple epiphyseal dysplasia with normal stature, club foot, and double layered patella caused by a DTDST mutation. Journal of medical genetics. 1999. PMID: 10465113
- Adam MP, Bick S, Mirzaa GM. SLC26A2-Related Multiple Epiphyseal Dysplasia. 1993. PMID: 20301483
- Superti-Furga A, Unger S. SLC26A2-Related Atelosteogenesis. 1993. PMID: 20301493
- Adam MP, Bick S, Mirzaa GM. Diastrophic Dysplasia. 1993. PMID: 20301524
- Adam MP, Bick S, Mirzaa GM. Achondrogenesis Type 1B. 1993. PMID: 20301689