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ADAMTSL4
ADAMTS like 4
The ADAMTSL4 gene provides instructions for a protein crucial in forming microfibrils within the extracellular matrix, playing a role in maintaining tissue structure, especially in the eyes. ADAMTSL4 encodes a protein released into the extracellular matrix, where it binds to other proteins like fibrillin-1 to facilitate microfibril assembly.
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, also known as ADAMTS like 4, is responsible for producing a protein that is widely distributed throughout the human body. This protein is secreted into the extracellular matrix (ECM), a complex network of proteins and molecules found in the spaces between cells. Within the ECM, the ADAMTSL4 protein interacts with other proteins, most notably fibrillin-1, to support the formation of thread-like structures called microfibrils. These microfibrils are fundamental to the structural integrity and organisation of various tissues.
Pathogenic variants in the ADAMTSL4 gene are linked to inherited conditions, primarily affecting the eyes, such as ectopia lentis. Understanding the role of ADAMTSL4 provides insight into the molecular basis of these conditions and the importance of microfibril assembly for tissue health.
What the gene does
The ADAMTSL4 gene provides instructions for synthesising a protein that contributes to the structural scaffolding of tissues. This protein is released from cells and integrates into the extracellular matrix, which is the non-cellular component of all tissues and organs, providing physical support and enabling cell communication. A key function of the ADAMTSL4 protein is its interaction with fibrillin-1. Fibrillin-1 proteins self-assemble and bind to other proteins to create microfibrils. Research indicates that ADAMTSL4 facilitates this process, promoting the proper assembly of microfibrils in numerous tissues throughout the body.
In the eyes, microfibrils form specialised 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. The proper functioning of the ADAMTSL4 protein is therefore essential for maintaining normal ocular structure and vision, as well as broader tissue integrity.
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Chromosome location
The ADAMTSL4 gene is located on chromosome 1, specifically at position 1q21.2. This genomic location specifies where the gene resides within the human genome. The gene provides the blueprint for a protein composed of 1074 amino acids.
Protein structure
The ADAMTSL4 protein is characterised by several distinct domains that contribute to its function. These include multiple thrombospondin type-1 (TSP type-1) domains and a PLAC domain. Specifically, the protein contains TSP type-1 1 (amino acids 48-93), 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). A notable Disordered region spans amino acids 77-342, suggesting flexibility in this part of the protein. At the C-terminus, a PLAC domain is found from amino acids 1029-1066. These domains mediate protein-protein interactions essential for its role in microfibril assembly.
Key variants
Genetic variations within the ADAMTSL4 gene can influence its protein product and subsequent function. Pathogenic variants, which are genetic changes linked to disease, can disrupt the normal assembly of microfibrils. These changes may lead to altered protein structure or reduced protein quantity, impacting its ability to interact with other extracellular matrix components like fibrillin-1. The specific type and location of a variant can dictate the severity and presentation 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.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.2237G>A | p.Arg746His | Pathogenic | ★★☆☆ | ADAMTSL4-related disorder |
c.2270del | p.Gly757fs | Pathogenic/Likely pathogenic | ★★☆☆ | ADAMTSL4-related disorder |
c.2270dup | p.Gly758fs | Pathogenic | ★★☆☆ | ADAMTSL4-related disorder |
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
Variants in the ADAMTSL4 gene are primarily associated with conditions affecting the eyes. One such condition is isolated ectopia lentis, where the lens in one or both eyes is dislocated from its normal position. This dislocation often results in vision problems such as nearsightedness, farsightedness, and astigmatism. Some pathogenic variants in ADAMTSL4 are also linked to ectopia lentis et pupillae, a condition characterised by displacement of both the lenses and the pupils, typically in opposite directions.
No disease links recorded for this gene in our reference set.
UK clinical status
Within the UK, the ADAMTSL4 gene is included on several NHS Genomic Medicine Service national panels. It is listed with a 'green' status for rare syndromic craniosynostosis or isolated multisuture synostosis (R100), structural eye disease (R36), and thoracic aortic aneurysm or dissection. A 'green' status indicates that there is sufficient evidence for the gene to be routinely assessed in diagnostic testing for these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ADAMTSL4 gene?
The ADAMTSL4 gene produces a protein that is crucial for the assembly of microfibrils within the extracellular matrix. These microfibrils are important for providing structural support to tissues, particularly the zonular fibres in the eye that hold the lens in place.
What health conditions are associated with variants in ADAMTSL4?
Variants in the ADAMTSL4 gene are mainly associated with eye conditions, including isolated ectopia lentis, where the eye's lens is dislocated, and ectopia lentis et pupillae, which involves dislocation of both the lens and the pupil.
How does ADAMTSL4 contribute to eye health?
In the eyes, the ADAMTSL4 protein helps form microfibrils that create zonular fibres. These fibres are essential for anchoring the eye's lens, ensuring it remains in its central position to facilitate clear vision.
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