ADAMTS18 — ADAM metallopeptidase with thrombospondin type 1 motif 18

The ADAMTS18 gene provides instructions for making a protein that acts like a pair of molecular scissors. This protein works outside of cells to cut and organize the structural framework that supports tissues, known as the extracellular matrix. It plays a very important role during the early development of the body, particularly in the proper formation and growth of the eyes. When a person inherits two mutated copies of the ADAMTS18 gene, the protein does not work correctly or is missing entirely. This disrupts the normal development of the eye, leading to a condition characterized by unusually small corneas (microcornea), displaced lenses, and early-onset cataracts. It also severely affects the retina, the light-sensitive tissue at the back of the eye, causing a progressive loss of vision known as cone-rod dystrophy, severe nearsightedness (myopia), and a high risk of retinal detachment. Currently, there is no cure for the vision loss caused by ADAMTS18 mutations. Management focuses on treating the specific symptoms, such as surgery for cataracts or retinal detachment, and using corrective lenses for refractive errors. Regular monitoring by an eye specialist is crucial to manage complications and preserve remaining vision for as long as possible.

Gene description: ADAMTS18 encodes a secreted zinc-dependent metalloproteinase belonging to the ADAMTS family, which plays a role in extracellular matrix remodeling and tissue development. Mutations in this gene are primarily associated with severe ocular developmental defects and early-onset retinal dystrophies, such as microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT).

Patient and family guide: The ADAMTS18 gene provides instructions for making a protein that acts like a pair of molecular scissors. This protein works outside of cells to cut and organize the structural framework that supports tissues, known as the extracellular matrix. It plays a very important role during the early development of the body, particularly in the proper formation and growth of the eyes. When a person inherits two mutated copies of the ADAMTS18 gene, the protein does not work correctly or is missing entirely. This disrupts the normal development of the eye, leading to a condition characterized by unusually small corneas (microcornea), displaced lenses, and early-onset cataracts. It also severely affects the retina, the light-sensitive tissue at the back of the eye, causing a progressive loss of vision known as cone-rod dystrophy, severe nearsightedness (myopia), and a high risk of retinal detachment. Currently, there is no cure for the vision loss caused by ADAMTS18 mutations. Management focuses on treating the specific symptoms, such as surgery for cataracts or retinal detachment, and using corrective lenses for refractive errors. Regular monitoring by an eye specialist is crucial to manage complications and preserve remaining vision for as long as possible.

Gene function: ADAMTS18 functions as a secreted zinc-dependent metalloproteinase that participates in the proteolysis of extracellular matrix components, such as fibronectin. It plays essential roles in morphogenetic events, organogenesis, and the regulation of cell migration, angiogenesis, and hemostatic balance during development.

Protein structure: The ADAMTS18 protein contains a signal peptide, a propeptide, a metalloprotease catalytic domain with a zinc-binding motif, a disintegrin-like domain, a central thrombospondin type 1 (TS) motif, a cysteine-rich domain, a spacer region, and five additional C-terminal TS repeats.

Molecular function: ADAMTS18 exhibits metalloendopeptidase activity, utilizing a zinc ion at its catalytic site to cleave specific extracellular matrix proteins. It binds to and proteolytically processes substrates like fibronectin, which regulates fibronectin fibrillogenesis and extracellular matrix organization. This proteolytic activity is crucial for modulating cell-matrix interactions, influencing cell migration, proliferation, and tissue morphogenesis. Additionally, it interacts with other matrix proteins like fibrillin-1, affecting the assembly of microfibrils and actin cytoskeletal dynamics.

Mutation spectrum: The mutation spectrum of ADAMTS18 includes homozygous missense mutations and nonsense mutations. These mutations are typically found in the prodomain, the metalloprotease catalytic domain, the disintegrin-like domain, and the cysteine-rich region, leading to premature protein truncation or loss of critical structural and functional integrity.

Clinical significance: Mutations in the ADAMTS18 gene cause a spectrum of ocular developmental abnormalities and retinal dystrophies. Homozygous missense and nonsense mutations lead to a loss of functional protein, which disrupts normal eye development and extracellular matrix organization. This results in anterior segment dysgenesis, including microcornea, ectopia lentis, and early-onset cataracts. In the posterior segment, it causes early-onset severe retinal degeneration, specifically cone-rod dystrophy, myopic chorioretinal atrophy, and an increased risk of rhegmatogenous retinal detachment. The condition is collectively known as microcornea, myopic chorioretinal atrophy, and telecanthus (MMCAT).

Inheritance: Autosomal Recessive

Chromosomal location: 16q23.1

Research and therapeutic approaches: Currently, there are no specific gene therapies or targeted treatments available for ADAMTS18-related inherited retinal diseases. Management is primarily supportive and multidisciplinary, focusing on treating ocular complications. This includes surgical interventions for cataracts, ectopia lentis, and retinal detachments, as well as the use of corrective lenses for severe refractive errors. Research into gene therapy for inherited retinal diseases is ongoing, but specific trials for ADAMTS18 have not yet been established.