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ADAMTS2
ADAM metallopeptidase with thrombospondin type 1 motif 2
The ADAMTS2 gene provides instructions for creating an enzyme crucial for processing procollagen molecules, which are essential precursors to the collagen fibres that provide strength and elasticity to connective tissues. The ADAMTS2 gene encodes an enzyme that performs a specific cleavage step on procollagen, enabling it to assemble into strong collagen fibrils.
ADAMTS2 is located on the long (q) arm of chromosome 5, at band 5q35.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ADAMTS2 gene, fully known as 'ADAM metallopeptidase with thrombospondin type 1 motif 2', plays a vital role in the formation and maintenance of connective tissues throughout the body. It provides the genetic blueprint for an enzyme involved in the processing of procollagen, which is the precursor molecule to collagen. Collagen is a fundamental component of various tissues, providing structural support, strength, and elasticity.
What the gene does
The ADAMTS2 gene directs the production of an enzyme that is instrumental in the maturation of collagen. Specifically, this enzyme is responsible for cleaving a short chain of amino acids from the N-terminus of procollagen molecules. This precise enzymatic 'cutting' is a necessary step for procollagen to correctly assemble into the robust, slender collagen fibrils found in connective tissues. Without proper processing by the ADAMTS2 enzyme, collagen molecules cannot form their characteristic strong structures, leading to defects in tissue integrity.
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Chromosome location
The ADAMTS2 gene is located on the long arm of chromosome 5, specifically at position 5q35.3. This chromosomal location dictates where the gene is situated within the human genome.
Protein structure
The ADAMTS2 protein comprises 1211 amino acids and features several distinct domains critical for its enzymatic function. These include a Peptidase M12B domain (amino acids 266-470) responsible for its metallopeptidase activity, and a Disintegrin domain (amino acids 480-560). It also contains multiple TSP type-1 domains, including TSP type-1 1 (amino acids 561-616), TSP type-1 2 (amino acids 854-912), TSP type-1 3 (amino acids 914-971), and TSP type-1 4 (amino acids 975-1029). A Cell attachment site (amino acids 691-693), a Spacer region (amino acids 723-851), a PLAC domain (amino acids 1059-1097), and a Disordered region (amino acids 1170-1191) further contribute to its structure and potential interactions.
Key variants
Variants within the ADAMTS2 gene can lead to alterations in the encoded enzyme, affecting its ability to correctly process procollagen. These genetic changes can range from single nucleotide substitutions to larger deletions or insertions, and their impact on protein function can vary significantly. Understanding these variants is crucial for assessing potential clinical implications related to connective tissue 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.100_130del | p.Pro34fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.102_123dup | p.Ala42fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.1360C>T | p.Gln454Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.137del | p.Pro46fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.1599dup | p.Asp535fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.1701G>A | p.Trp567Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.1822C>T | p.Gln608Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1977C>A | p.Cys659Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.2372del | p.Met791fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
c.2398G>T | p.Glu800Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ehlers-Danlos syndrome, dermatosparaxis type |
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 ADAMTS2 gene are primarily associated with the dermatosparaxis type of Ehlers-Danlos syndrome. This condition is an inherited connective tissue disorder characterised by features such as extremely fragile and soft skin that may appear saggy or wrinkled, and an increased tendency for bruising. Ehlers-Danlos syndrome encompasses a group of disorders that impact the connective tissues supporting various organs and structures.
Inheritance pattern
Conditions caused by pathogenic ADAMTS2 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
In the UK, the ADAMTS2 gene is included in the NHS Genomic Medicine Service's national test directory. It is listed on the 'Ehlers Danlos syndrome with a likely monogenic cause' panel (R101), indicating its relevance for diagnostic testing in individuals suspected of having this condition.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ADAMTS2 gene?
The ADAMTS2 gene provides instructions for an enzyme that processes procollagen molecules. This processing step, which involves cleaving a specific protein segment, is vital for procollagen to correctly assemble into strong collagen fibrils that provide structural support to tissues.
What condition is associated with variants in the ADAMTS2 gene?
Variants in the ADAMTS2 gene are primarily associated with the dermatosparaxis type of Ehlers-Danlos syndrome. This is a connective tissue disorder characterised by fragile, sagging skin and easy bruising.
How is dermatosparaxis Ehlers-Danlos syndrome inherited?
The dermatosparaxis type of Ehlers-Danlos syndrome caused by ADAMTS2 variants follows an autosomal recessive inheritance pattern. This means an individual must inherit two copies of the altered gene (one from each parent) to develop the condition.
References
- Kelwick R, Desanlis I, Wheeler GN. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family. Genome biology. 2015. PMID: 26025392
- Le Goff C, Cormier-Daire V. The ADAMTS(L) family and human genetic disorders. Human molecular genetics. 2011. PMID: 21880666
- Colige A, Nuytinck L, Hausser I. Novel types of mutation responsible for the dermatosparactic type of Ehlers-Danlos syndrome (Type VIIC) and common polymorphisms in the ADAMTS2 gene. The Journal of investigative dermatology. 2004. PMID: 15373769
- Wang WM, Lee S, Steiglitz BM. Transforming growth factor-beta induces secretion of activated ADAMTS-2. A procollagen III N-proteinase. The Journal of biological chemistry. 2003. PMID: 12646579
- Colige A, Sieron AL, Li SW. Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene. American journal of human genetics. 1999. PMID: 10417273