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ADAMTSL4
ADAMTS like 4
The ADAMTSL4 gene provides instructions for a protein crucial in forming the extracellular matrix, particularly microfibrils, and is linked to ocular conditions like ectopia lentis. ADAMTSL4 encodes a protein integral to the extracellular matrix, a support structure for cells.
ADAMTSL4 is located on the long (q) arm of chromosome 1, at band 1q21.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The ADAMTSL4 gene, full name ADAMTS like 4, is responsible for producing a protein that plays a key role in the formation and maintenance of the extracellular matrix. This complex network of proteins and other molecules provides structural and biochemical support to cells in tissues throughout the body.
Disruptions in the ADAMTSL4 gene's function are associated with specific inherited conditions, primarily affecting the eye. Understanding the role of ADAMTSL4 helps in comprehending the underlying mechanisms of these conditions.
What the gene does
The protein produced from the ADAMTSL4 gene is secreted from cells into the extracellular matrix. Here, it interacts with other proteins, most notably fibrillin-1. Fibrillin-1 proteins combine to form thread-like structures called microfibrils, which are essential components of connective tissues.
Research indicates that the ADAMTSL4 protein binds to fibrillin-1 to promote the proper assembly of these microfibrils across various tissues. In the eye, microfibrils arrange into small bundles known as zonular fibres. These fibres are crucial for holding the eye's lens in its correct central position, enabling it to focus light effectively. Consequently, any impairment in ADAMTSL4 function can impact microfibril formation and lead to structural issues.
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Chromosome location
The ADAMTSL4 gene is located on chromosome 1 at position 1q21.2. This specific genomic address helps to identify its position within the human genome. The gene contains instructions for synthesising a protein composed of 1074 amino acids.
Protein structure
The ADAMTSL4 protein is characterised by several distinct domains. At the N-terminus, it features a TSP type-1 domain (amino acids 48-93). A significant portion of the protein is a Disordered Region (amino acids 77-342). Further along, there are multiple additional TSP type-1 domains: TSP type-1 2 (amino acids 723-782), TSP type-1 3 (amino acids 783-842), TSP type-1 4 (amino acids 845-909), TSP type-1 5 (amino acids 910-969), and TSP type-1 6 (amino acids 970-1026). The protein concludes with a PLAC domain (amino acids 1029-1066) at its C-terminus.
Key variants
Variants in the ADAMTSL4 gene can affect the structure and function of the ADAMTSL4 protein. These genetic changes can range from small alterations in the DNA sequence to larger structural rearrangements. Such variants may lead to a non-functional or improperly functioning protein, thereby disrupting its role in microfibril assembly and extracellular matrix integrity.
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.1143del | p.Glu382fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1213C>T | p.Gln405Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1480C>T | p.Arg494Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1712C>A | p.Ser571Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Isolated ectopia lentis |
c.2008C>T | p.Arg670Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Ectopia lentis 2, isolated, autosomal recessive |
c.2021_2022del | p.Ser674fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2087C>A | p.Ser696Ter | Pathogenic | ★★☆☆ | not provided |
c.2270del | p.Gly757fs | Pathogenic/Likely pathogenic | ★★☆☆ | Ectopia lentis 2, isolated, autosomal recessive |
c.2270dup | p.Gly758fs | Pathogenic | ★★☆☆ | Ectopia lentis et pupillae |
c.2375G>A | p.Trp792Ter | Pathogenic | ★★☆☆ | not provided |
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 ADAMTSL4 gene are known to cause inherited conditions, primarily affecting the eye. One such condition is isolated ectopia lentis, where the lens in one or both eyes is displaced from its normal position. This often results in vision problems, including short-sightedness, long-sightedness, and astigmatism. Some variants in ADAMTSL4 can also lead to ectopia lentis et pupillae, a condition where both the lenses and pupils are displaced, typically in opposing directions.
No disease links recorded for this gene in our reference set.
UK clinical status
The ADAMTSL4 gene is included in several NHS Genomic Medicine Service national test panels, indicating its clinical relevance within the UK healthcare system. It is listed on the Rare syndromic craniosynostosis or isolated multisuture synostosis panel (green R100), the Structural eye disease panel (green R36), and the Thoracic aortic aneurysm or dissection panel (green), signifying its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ADAMTSL4 protein?
The ADAMTSL4 protein is secreted into the extracellular matrix where it binds to fibrillin-1. It promotes the proper assembly of microfibrils, which are essential components of connective tissues, particularly important for holding the eye's lens in place.
What conditions are associated with variants in ADAMTSL4?
Pathogenic variants in the ADAMTSL4 gene are primarily associated with inherited eye conditions such as isolated ectopia lentis, where the eye's lens is displaced. Some variants can also cause ectopia lentis et pupillae, involving displacement of both the lens and pupil.
How does ADAMTSL4 relate to eye health?
In the eyes, ADAMTSL4-mediated microfibrils form zonular fibres. These fibres are crucial for maintaining the central position of the eye's lens, which is necessary for clear vision. Dysfunction of ADAMTSL4 can lead to lens displacement and related vision problems.
References
- Gabriel LA, Wang LW, Bader H. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Investigative ophthalmology & visual science. 2012. PMID: 21989719
- Chandra A, Aragon-Martin JA, Hughes K. A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis. Investigative ophthalmology & visual science. 2012. PMID: 22736615
- Hubmacher D, Apte SS. Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function. Cellular and molecular life sciences : CMLS. 2011. PMID: 21858451
- Christensen AE, Fiskerstrand T, Knappskog PM. A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. Investigative ophthalmology & visual science. 2010. PMID: 20702823