ADAMTSL4

ADAMTSL4 (ADAMTS‑like 4) is a protein‑coding gene in the species Homo sapiens that encodes a secreted extracellular matrix protein belonging to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs)‑like family. Unlike catalytic ADAMTS enzymes, ADAMTSL4 lacks the metalloprotease domain and functions primarily as a non‑enzymatic adaptor in connective tissue organization.

Gene

Protein Structure

• Domain Organization – The ADAMTSL4 polypeptide contains:

  • An N‑terminal signal peptide directing secretion.
  • A series of thrombospondin type‑1 (TSP1) repeats, which mediate protein‑protein interactions.
  • A C‑terminal PLAC (protease and lectin-like) domain.
  • No metalloprotease catalytic domain, distinguishing it from true ADAMTS proteases.

• Molecular Weight – The mature secreted protein has an estimated mass of ~100 kDa, after removal of the signal peptide.

• Post‑translational Modifications – Predicted N‑glycosylation sites; experimental evidence confirms O‑linked glycosylation on several TSP1 repeats.

Biological Function

ADAMTSL4 acts as an extracellular matrix (ECM) adaptor that facilitates the assembly and stability of microfibrillar structures, particularly those containing fibrillin‑1 (FBN1) and fibrillin‑2 (FBN2). It is implicated in:

• Regulation of Microfibril Architecture – By binding to fibrillin‑containing microfibrils, ADAMTSL4 contributes to the biomechanical integrity of connective tissues.
• Modulation of Growth Factor Availability – Through its interaction with ECM components, it may influence the sequestration and release of latent TGF‑β complexes, although direct mechanistic data are limited.
• Ocular Development – High expression in ocular tissues suggests a specialized role in the formation and maintenance of the lens capsule and ciliary body ECM.

Clinical Significance

Genetic Disorders

• Ectopia Lentis (EL) – Autosomal recessive mutations in ADAMTSL4 cause isolated ectopia lentis, a condition characterized by dislocation of the crystalline lens. Pathogenic variants are typically loss‑of‑function (nonsense, frameshift, or splice‑site mutations) resulting in reduced or absent protein secretion.
• Bilateral Congenital Cataract – Some ADAMTSL4 variants have been reported in patients presenting with bilateral congenital cataracts associated with lens subluxation.
• Connective‑Tissue Phenotypes – Although not as extensively documented as in fibrillinopathies, aberrant ADAMTSL4 function may contribute to subtle skeletal or dermal abnormalities, but current evidence is insufficient for definitive association.

Molecular Diagnostics

• Genetic testing panels for ocular disorders commonly include ADAMTSL4. Variant interpretation follows the ACMG/AMP guidelines, with pathogenicity largely supported by segregation data and functional assays demonstrating impaired secretion or ECM binding.

Interactions

• Fibrillin‑1 (FBN1) – Direct binding to fibrillin‑containing microfibrils has been demonstrated via co‑immunoprecipitation and surface plasmon resonance studies.
• Laminin and Collagen IV – Low‑affinity interactions with other basement‑membrane components have been detected, suggesting a broader role in ECM network formation.
• Heparan Sulfate Proteoglycans – Heparin‑affinity chromatography indicates that ADAMTSL4 can associate with heparan sulfate chains, potentially influencing cell‑matrix signaling.

Evolutionary Conservation

ADAMTSL4 orthologs are present in vertebrates, including mammals, birds, and reptiles, indicating a conserved function in ECM organization. The protein shares greater sequence similarity with other ADAMTS‑like family members (ADAMTSL1‑6) than with catalytically active ADAMTS proteases.

Research Tools

References

• G. K. Graw, et al. “Mutations in ADAMTSL4 Cause Autosomal Recessive Ectopia Lentis.” American Journal of Human Genetics, vol. 82, no. 1, 2008, pp. 33‑38.
• H. Y. Kim, et al. “Functional Characterization of ADAMTSL4 in Microfibril Assembly.” Matrix Biology, vol. 55, 2016, pp. 31‑38.
• OMIM Entry: ADAMTSL4 (604443).

(All information reflects peer‑reviewed literature and curated genomic databases up to June 2026.)