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Normal Function
The ADAMTSL4 gene provides instructions for making a protein that is found throughout the body. The ADAMTSL4 protein is released from cells into the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. The ADAMTSL4 protein binds to other proteins within the extracellular matrix. One of these proteins is called fibrillin-1. Fibrillin-1 proteins bind to each other and to other proteins to form threadlike filaments called microfibrils. Research suggests that ADAMTSL4 binds to fibrillin-1 to promote microfibril assembly in many tissues. Within the eyes, microfibrils form small bundles called zonular fibers that hold the lenses of the eyes in their central position. The lens is a clear structure at the front of the eye that helps focus light.
Health Conditions Related to Genetic Changes
Isolated ectopia lentis
Changes in the ADAMTSL4 gene have been found to cause isolated ectopia lentis. Genetic changes that cause disease are called pathogenic variants. In people with ectopia lentis, the lens in one or both eyes is out of place (ectopic). This often leads to vision problems including nearsightedness (myopia), farsightedness (hyperopia), and an irregular curvature of the front of the eye (astigmatism). Affected indviduals may also develop clouding of the lenses (cataracts) or increased pressure in the eyes (glaucoma) at an early age.
Most pathogenic variants in the ADAMTSL4 gene cause cells to produce a version of the protein that is abnormally short and nonfunctional. Other variants lead to the substitution of one protein building block (amino acid) for another in the ADAMTSL4 protein. Without enough functional ADAMTSL4 proteins, fibrillin-1 cannot effectively form microfibrils. As a result, there are fewer microfibrils available to form zonular fibers. Without these zonular fibers, the lens becomes displaced, leading to the vision problems that are characteristic of isolated ectopia lentis.
While the ADAMTSL4 protein is found throughout the body, it is thought that other proteins can make up for the loss of ADAMTSL4 protein in tissues other than the eyes, which likely explains why only the eyes are affected in people with isolated ectopia lentis.
More About This Health ConditionOther disorders
Some pathogenic variants in the ADAMTSL4 gene cause an eye condition called ectopia lentis et pupillae. In people with this condition, both the lenses and the pupils are ectopic. The pupils are the black openings at the center of the eyes. In affected individuals, the lenses and the pupils are usually displaced in opposite directions. This condition is often apparent at birth, although mild cases might not get diagnosed until adulthood. People with ectopia lentis et pupillae have eye and vision problems that are similar to those seen in people with isolated ectopia lentis.
The ADAMTSL4 gene variants that cause ectopia lentis et pupillae decrease the production of functional micofibrils, which prevents the formation of zonular fibers and the proper anchoring of certain structures in the eyes. In some cases, the same variant can cause isolated ectopic lentis in some people and ectopia lentia et pupillae in others. It is unclear why some ADAMTSL4 gene variants affect people differently.
Other Names for This Gene
- DKFZP434K1772
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Chandra A, Aragon-Martin JA, Hughes K, Gati S, Reddy MA, Deshpande C, Cormack G, Child AH, Charteris DG, Arno G. A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis. Invest Ophthalmol Vis Sci. 2012 Jul 24;53(8):4889-96. doi: 10.1167/iovs.12-9874. Citation on PubMed
- Christensen AE, Fiskerstrand T, Knappskog PM, Boman H, Rodahl E. A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. Invest Ophthalmol Vis Sci. 2010 Dec;51(12):6369-73. doi: 10.1167/iovs.10-5597. Epub 2010 Aug 11. Citation on PubMed
- Gabriel LA, Wang LW, Bader H, Ho JC, Majors AK, Hollyfield JG, Traboulsi EI, Apte SS. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci. 2012 Jan 31;53(1):461-9. doi: 10.1167/iovs.10-5955. Citation on PubMed or Free article on PubMed Central
- Hubmacher D, Apte SS. Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function. Cell Mol Life Sci. 2011 Oct;68(19):3137-48. doi: 10.1007/s00018-011-0780-9. Epub 2011 Aug 20. Citation on PubMed or Free article on PubMed Central
- Rodahl E, Mellgren AEC, Boonstra NE, Knappskog PM. ADAMTSL4-Related Eye Disorders. 2012 Feb 16 [updated 2020 Jul 9]. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK84111/ Citation on PubMed
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