The βIG-H3 gene, also known as
TGFBI, was
first identified by Skonier et al.
1 who isolated it by
screening a cDNA library made from a human lung adenocarcinoma cell
line (A549) that had been treated with TGF-β. The βIG-H3 protein is
composed of 683 amino acids containing short amino acid regions
homologous to similar motifs in
Drosophila fasciclin-I and
four homologous internal domains. We have reported that βIG-H3
mediates corneal epithelial cell adhesion through α3β1 integrin,
and we have identified two motifs interacting with α3β1 integrin
within repeat domains of βIG-H3.
2 Mutations of βIG-H3
were demonstrated to be responsible for 5q31-linked human autosomal
dominant corneal dystrophies, such as granular (GCD),
Reis-Bückler (RBCD), lattice type I (LCD-1), and Avellino (ACD)
corneal dystrophies.
3 These diseases are characterized by
progressive accumulation of protein deposits in the cornea, leading to
severe visual impairment. Depending on the mutation, the accumulations
form rod-shaped crystalloid structures, amyloid, a combination of
rod-shaped bodies with amyloid, or curly fibers.
4 The
appearance of the opacities depends on the location and nature of the
corneal deposits, and this is presumably influenced by the
three-dimensional structure of the mutant proteins. Although the
immunohistochemical studies
5 6 demonstrated that βIG-H3
is strongly stained in the pathologic deposits in all βIG-H3-related
corneal dystrophies, the role of the different mutations in the
formation of different types of deposits is largely unknown. Even, the
structure of wild-type βIG-H3 and its interaction with other
extracellular matrix (ECM) proteins are not known. To gain insight into
the mechanism of how mutations of βIG-H3 lead to the accumulation of
pathologic deposits in 5q31-linked corneal dystrophies, we first
studied the molecular properties of βIG-H3, including the structure
and interactions with other ECM proteins, and then the effects of
mutations on these properties.