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Granular and lattice deposits in corneal dystrophy caused by R124C mutation of TGFBIp.

ABSTRACT: Both granular and lattice deposits are present in Avellino corneal dystrophy (ACD), primarily associated with the R124H mutation of transforming growth factor-?-induced (TGFBIp). We investigated the presence of these deposits in other TGFBI mutations and the use of Thioflavin-T (ThT), a fluorescent amyloid stain for characterizing corneal amyloid deposits.Surgical corneal specimens of 3 unrelated patients clinically diagnosed with ACD were studied. Corneal sections from normal individuals and patients with prior lattice corneal dystrophy (LCD) were used as controls. Histochemical studies were performed with Congo red and Masson trichrome stains, and fluorescent imaging with scanning laser confocal microscopy was performed for ThT and anti-TGFBIp antibody staining.Clinical and histopathological findings supported the diagnoses of ACD in these 3 cases in whom granular deposits stained with Masson trichrome and lattice deposits stained with ThT and Congo red showed birefringence and dichroism as expected. However, genotyping revealed a heterozygous R124C mutation in each case. In addition to classical stromal deposits, unique subepithelial TGFBIp aggregates, which stain with neither ThT nor trichrome, were observed. In control LCD sections, stromal deposits were stained with ThT but not with trichrome, confirming lack of granular deposits.Our results demonstrate that both granular and lattice corneal deposits can be associated with R124C mutation in addition to the more common R124H mutation. An additional feature of nonhyaline, nonamyloid, TGFBIp subepithelial deposits might substantiate the categorization of such cases as a variant form of ACD. This study further validates ThT staining for detection of amyloid TGFBIp deposits.

SUBMITTER: Patel DA

PROVIDER: S-EPMC2965268 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Granular and lattice deposits in corneal dystrophy caused by R124C mutation of TGFBIp.

Patel Dhara A DA Chang Shu-Hong SH Harocopos George J GJ Vora Smita C SC Thang Diep Huu DH Huang Andrew J W AJ

Cornea 20101101 11

<h4>Purpose</h4>Both granular and lattice deposits are present in Avellino corneal dystrophy (ACD), primarily associated with the R124H mutation of transforming growth factor-β-induced (TGFBIp). We investigated the presence of these deposits in other TGFBI mutations and the use of Thioflavin-T (ThT), a fluorescent amyloid stain for characterizing corneal amyloid deposits.<h4>Methods</h4>Surgical corneal specimens of 3 unrelated patients clinically diagnosed with ACD were studied. Corneal section ...[more]

PMID: 20697279

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Project description:PURPOSE: To report the clinical, ophthalmic, and genetic characteristics for lattice corneal dystrophy type I (LCDI) in a Chilean family. METHODS: Six affected family members were examined clinically including visual acuity, color cornea photography, applanation tonography, and fundoscopy. Genomic DNA was extracted from peripheral leukocytes from six affected and three unaffected members of a family with lattice corneal dystrophy type I. Exon 4 of the transforming growth factor-induced gene (TGFBI) was screened for the most frequent mutation, R124C, in the proband by sequencing. We also designed a rapid polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the same mutation, amplifying exon 4 and digesting with PstI restriction enzyme. Using this strategy, we analyzed the mutation in six affected and three healthy family members. RESULTS: Three generations of family members were positively diagnosed with lattice corneal dystrophy. Six participants demonstrated LCD1 in both eyes, most of whom were symmetric. Age at onset of symptoms was variable (3-42 years old). Moreover, in this family, the age of onset of the disease decreased in succeeding generations, which could be interpreted as anticipation. Visual acuity varied from 1.0 to 0.13. Two patients, ages 69 and 44 years old, demonstrated a degree of severity "Bad" according to best-corrected vision and corneal commitment. The exon 4 sequence of TGFBI of the proband exhibits the heterozygous single-nucleotide mutation, C417T, leading to amino acid substitution (R124C) in the encoded TGF-induced protein. Using PCR-RFLP, we confirmed the heterozygous mutation in six affected family members and excluded it in three healthy members. CONCLUSIONS: The R124C mutation in TGFBI cosegregated with LCD type I in the investigated family. This is the first report of a molecular analysis of LCD type I in Chilean patients. The early onset affected persons in the fourth generation raises the possibility of anticipation.

Project description:PurposeTo describe clinical data and to characterize mutations in the transforming growth factor beta-induced (TGFBI) gene in patients from three unrelated Chilean families with lattice corneal dystrophy type I (LCDI).MethodsSnellen acuity tests, anterior segment slit lamp examinations, dilated fundus evaluations, and tonometry were performed for seven patients--five females and two males belonging to three unrelated families--affected with lattice corneal dystrophy Type I. Genomic DNA was also extracted from peripheral leukocytes from the seven patients and four healthy relatives. The 417C>T mutation (R124C) was screened using PCR-RFLP for the seven patients and four healthy relatives. Exons 11, 12, 13, and 14 were sequenced in one patient not carrying the mutation in codon 124. Comparison of phenotype to genotype was performed.ResultsThe seven patients studied exhibited LCDI in both eyes, most of which were symmetric. Affected individuals demonstrated progression from central subepithelial needlelike deposits and polymorphic anterior stromal opacities. The age at onset of symptoms varied between six to 15 years old in Family One; the patient in Family Two was five years old and the patient in Family Three was 21 years old. Visual acuity varied from 1.0 to 0.05. Two patients, aged 50 and 45 years, underwent penetrating keratoplasty in both eyes, and two patients, aged 47 and 24 years, underwent penetrating keratoplasty in one eye. The only patient in Family Three exhibited a somewhat distinct phenotype, with yellowish discoloration in the anterior stroma and fewer, but thicker lattice lines than the patients in Families One and Two. Screening for the mutation C>T at the nucleotide position 417 (R124C) in exon 4 in the three families revealed the heterozygous R124C mutation in Families One and Two. In Family Two, the mutation was a de novo mutation, as neither parent was a carrier. Screening by sequencing analysis for mutation in exons 11, 12, 13, and 14 in the affected patient in Family Three revealed a heterozygous A1762G mutation (H572R) in exon 13.ConclusionsThis is the second report of the 417C>T mutation and the first report of 1762 A>G mutation (H572R) in Chilean patients. The H572R mutation identified is associated with a distinct lattice corneal dystrophy type I phenotype.

Dataset Information

Granular and lattice deposits in corneal dystrophy caused by R124C mutation of TGFBIp.

Publications

Granular and lattice deposits in corneal dystrophy caused by R124C mutation of TGFBIp.

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