Novel and known mutations of TGFBI, their genotype-phenotype correlation and structural modeling in 3 Chinese families with lattice corneal dystrophy.
OBJECTIVE
To report novel transforming growth factor beta-induced (TGFBI) mutations responsible for lattice corneal dystrophy (LCD), the associated genotype-phenotype correlation, and structural changes in the mutant proteins in three Chinese families.


METHODS
Three unrelated Chinese families were diagnosed as Type I LCD. Mutations in TGFBI were detected by sequencing all of the 17 exons and splice sites of the gene. Phenotype, including corneal erosions, and opacification in the families were compared. Structural changes of the mutant proteins were modeled. One hundred healthy volunteers were recruited as controls for sequence analysis of TGFBI.


RESULTS
Two novel mutations, c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) in TGFBI were identified in Family 1. Two known hotspot mutations, c. 531C>T (p. Arg124Cys) and c.1876A>G (p.His572Arg), were revealed in Family 2 and Family 3, respectively. Sequence analysis in the 100 healthy control subjects, the unaffected members in Family 1, and evolutionary alignment showed that the novel mutations occurred in the conserved amino acids. Structural modeling revealed changes in the 2nd structure of the mutant proteins, but did not detect gross structural changes. Mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were present in the corneas with sever opacification.


CONCLUSIONS
The novel mutations c.(1702G>C and 1706T>A; p.Arg514Pro and Phe515Leu), c. 531C>T (p. Arg124Cys), c.1876A>G (p.His572Arg) in TGFBI were responsible for LCD in the 3 families. Mutations c.(1702G>C and 1706T>A) (p.Arg514Pro and Phe515Leu) and the c. 531C>T (p. Arg124Cys) were associated with more severe LCD phenotypes in the families. These results provide more data for molecular diagnosis and prognosis of the disease.
Zhong
Xingwu
X
Zhongshan Ophthalmic Center and State Key laboratory of ophthalmology, Sun Yat-Sen University, Guangzhou, P.R.China.
Chen
Suqin
S
Huang
Weijun
W
Yang
Jun
J
Chen
Xiaolian
X
Zhou
Yan
Y
Zhou
Qiang
Q
Wang
Yiming
Y
D000328:Adult; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D002681:China; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000737:chemistry* / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016415:Sequence Alignment; D016212:Transforming Growth Factor beta / Q000737:chemistry* / Q000235:genetics*; D014792:Visual Acuity; D055815:Young Adult; D000099222:betaIG-H3 Protein
D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein