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Novel and known mutations of TGFBI, their genotype-phenotype correlation and structural modeling in 3 Chinese families with lattice corneal dystrophy.

Zhong X, Chen S, Huang W, Yang J, Chen X, Zhou Y, Zhou Q, Wang Y - Mol. Vis. (2010)

Bottom Line: Structural modeling revealed changes in the 2nd structure of the mutant proteins, but did not detect gross structural changes.Arg124Cys) were associated with more severe LCD phenotypes in the families.These results provide more data for molecular diagnosis and prognosis of the disease.

View Article: PubMed Central - PubMed

Affiliation: Zhongshan Ophthalmic Center and State Key laboratory of ophthalmology, Sun Yat-Sen University, Guangzhou, P.R.China.

ABSTRACT

Purpose: 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.

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Related in: MedlinePlus

Pedigrees of Family 1, 2, and 3. The closed symbols represent individuals affected by the LCD and the open symbols represent those who are unaffected. Arrowheads denote probands. Asterisks point to members analyzed in the study.
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f1: Pedigrees of Family 1, 2, and 3. The closed symbols represent individuals affected by the LCD and the open symbols represent those who are unaffected. Arrowheads denote probands. Asterisks point to members analyzed in the study.

Mentions: Five members from Family 1, four members from Family 2, one member from Family 3, and one hundred healthy volunteers (Han ethnicity) in clinic of Zhongshan Ophthalmic Center were recruited for this study. This study was approved by the Review Board of Sun Yat-Sen University. The principles outlined in the Declaration of Helsinki, such as participant safety, clinical trial registration, post-study access, usage of data and human tissues, compensating participants with research-related injury, were followed. Pedigrees of the three families were constructed (Figure 1). Among the three families, Family 1 and Family 2 came from Guangdong province, in the south of China, and Family 3 came from Sichuan province, in Western China. All three families are of Han ethnicity. Owing to the availability of samples, ten members of the families were analyzed (III:2, III:3, III:4, IV:2, IV:3 in Family 1; I:1, II:4, II:6, III:3 in Family 2; and II:2 in Family 3; Figure 1). No consanguinity between the families was found in the family histories. Visual acuity, slit lamp microscopy, and funduscopic examinations were performed by ophthalmologists (X.Z. and J.Y.). Blood samples were collected for DNA isolation. All the individuals included in the study underwent clinical examination before the molecular investigation. Systemic amyloidosis was excluded in all of the affected family members. One hundred healthy volunteers (Han ethnicity) were recruited as controls for sequence analysis of TGFBI. These control subjects were free of corneal opacity and epithelial defect, which was confirmed by slit-lamp microscopy.


Novel and known mutations of TGFBI, their genotype-phenotype correlation and structural modeling in 3 Chinese families with lattice corneal dystrophy.

Zhong X, Chen S, Huang W, Yang J, Chen X, Zhou Y, Zhou Q, Wang Y - Mol. Vis. (2010)

Pedigrees of Family 1, 2, and 3. The closed symbols represent individuals affected by the LCD and the open symbols represent those who are unaffected. Arrowheads denote probands. Asterisks point to members analyzed in the study.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2822555&req=5

f1: Pedigrees of Family 1, 2, and 3. The closed symbols represent individuals affected by the LCD and the open symbols represent those who are unaffected. Arrowheads denote probands. Asterisks point to members analyzed in the study.
Mentions: Five members from Family 1, four members from Family 2, one member from Family 3, and one hundred healthy volunteers (Han ethnicity) in clinic of Zhongshan Ophthalmic Center were recruited for this study. This study was approved by the Review Board of Sun Yat-Sen University. The principles outlined in the Declaration of Helsinki, such as participant safety, clinical trial registration, post-study access, usage of data and human tissues, compensating participants with research-related injury, were followed. Pedigrees of the three families were constructed (Figure 1). Among the three families, Family 1 and Family 2 came from Guangdong province, in the south of China, and Family 3 came from Sichuan province, in Western China. All three families are of Han ethnicity. Owing to the availability of samples, ten members of the families were analyzed (III:2, III:3, III:4, IV:2, IV:3 in Family 1; I:1, II:4, II:6, III:3 in Family 2; and II:2 in Family 3; Figure 1). No consanguinity between the families was found in the family histories. Visual acuity, slit lamp microscopy, and funduscopic examinations were performed by ophthalmologists (X.Z. and J.Y.). Blood samples were collected for DNA isolation. All the individuals included in the study underwent clinical examination before the molecular investigation. Systemic amyloidosis was excluded in all of the affected family members. One hundred healthy volunteers (Han ethnicity) were recruited as controls for sequence analysis of TGFBI. These control subjects were free of corneal opacity and epithelial defect, which was confirmed by slit-lamp microscopy.

Bottom Line: Structural modeling revealed changes in the 2nd structure of the mutant proteins, but did not detect gross structural changes.Arg124Cys) were associated with more severe LCD phenotypes in the families.These results provide more data for molecular diagnosis and prognosis of the disease.

View Article: PubMed Central - PubMed

Affiliation: Zhongshan Ophthalmic Center and State Key laboratory of ophthalmology, Sun Yat-Sen University, Guangzhou, P.R.China.

ABSTRACT

Purpose: 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.

Show MeSH
Related in: MedlinePlus