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Clinical and Ultrastructural Studies of Gelatinous Drop-Like Corneal Dystrophy (GDLD) of a Patient with TACSTD2 Gene Mutation.

ABSTRACT: Purpose:To describe clinical, molecular genetics, histopathologic and ultrastructural findings of gelatinous drop-like corneal dystrophy (GDLD) (OMIM #204870) in a Sudanese patient. Method:An ocular examination revealed the onset of GDLD in a Sudanese patient (50?years old) at King Khalid Specialist Hospital, Riyadh. The 333 sequence variants in 13 GDLD genes of a DNA sample were screened by Asper Ophthalmics Ltd. It was further confirmed by sequencing. The patient had undergone a penetrating keratoplasty in the right eye. The corneal tissue was processed for histopathology and ultrastructural studies. Results:Slit-lamp observation showed grayish-white multiple superficial corneal nodules of various sizes in the left and right eye. Both corneas became clear after the surgery. The GDLD deposits in the subepithelial region and in the anterior stroma were confirmed by PAS staining and their apple-green birefringence under polarized light. Ultrastructurally, the amyloid fibrils were very thin and grouped in whorl-like structures, which caused splits between and within the stromal lamellae. Collagen fibrils (CFs) and keratocytes had degenerated. A homozygous c.355T?>?A mutation in exon 1 of the TACSTD2 (M1S1) gene was detected, and alteration of the amino acid (p.Cysl19Ser in NCBI entry NP_002344.2) was observed. Conclusion:In our patient with GDLD, a "c.355T?>?A" mutation in exon 1 of TACSTD2 was detected and believed to be responsible for the alteration of the amino acid leading to the formation of the amyloid deposits. The deposits caused the ultrastructural degeneration of epithelium, Bowman's layer, stroma, and keratocytes of the GDLD cornea.

SUBMITTER: Masmali A

PROVIDER: S-EPMC6724435 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Clinical and Ultrastructural Studies of Gelatinous Drop-Like Corneal Dystrophy (GDLD) of a Patient with <i>TACSTD</i>2 Gene Mutation.

Masmali Ali A Alkanaan Aljoharah A Alkatan Hind M HM Kirat Omar O Almutairi Abdullah Ayidh AA Almubrad Turki T Akhtar Saeed S

Journal of ophthalmology 20190820

<h4>Purpose</h4>To describe clinical, molecular genetics, histopathologic and ultrastructural findings of gelatinous drop-like corneal dystrophy (GDLD) (OMIM #204870) in a Sudanese patient.<h4>Method</h4>An ocular examination revealed the onset of GDLD in a Sudanese patient (50 years old) at King Khalid Specialist Hospital, Riyadh. The 333 sequence variants in 13 GDLD genes of a DNA sample were screened by Asper Ophthalmics Ltd. It was further confirmed by sequencing. The patient had undergone a ...[more]

PMID: 31534795

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Project description:PURPOSE: To study the clinical, histological, in vivo confocal microscopic, and molecular profile in a family with gelatinous drop-like corneal dystrophy (GDLD) from north India. METHODS: Two siblings from a consanguineous family presented with clinical features analogous to GDLD. Detailed clinical evaluations were performed for all the available affected and unaffected members of this family. In vivo confocal microscopy and histology was done wherever necessary. DNA isolated from peripheral blood samples was subjected to polymerase chain reaction (PCR) followed by direct sequencing to detect mutations in the tumor-associated calcium signal transducer 2 (TACSTD2) gene. Protein modeling studies were done to asses the effect of the mutation on the protein structure. RESULTS: The diagnosis of GDLD was established in the patient and the affected sibling on slit-lamp examinations, which revealed mulberry-like opacities in the subepithelium and anterior stroma that were confirmed on histopathology. The findings of the in vivo confocal microscopy were consistent with those reported in previous reports. Sequencing TACSTD2 revealed a novel homozygous missense mutation c.356G>A, leading to amino acid substitution C119Y in the two affected siblings. The mutation was found to be pathogenic on Sorting Intolerant From Tolerant (SIFT) analysis and was not found in normal controls and unaffected individuals of the family. A synonymous, previously reported, single nucleotide polymorphism (SNP; rs13267) was also seen in all the individuals of the family. Protein modeling studies involving wild-type and mutant protein indicated an exposed cysteine residue in the mutant protein. CONCLUSIONS: A novel TACSTD2 C119Y mutation leading to an amino acid substitution was identified in two affected siblings of a family. Protein modeling studies revealed an exposed cysteine residue, which might cause interchain disulfide bond formation and protein aggregation leading to disturbed cell junctions of the corneal epithelium.

Project description:BackgroundReis-Bücklers corneal dystrophy (RBCD) was consistently reported as a corneal dystrophy only affected Bowman's layer and superficial corneal stroma, and superficial keratectomy was a recommendation surgery for treatment in literatures. The study reported new histopathological and ultrastructural findings in RBCD caused by the Arg124Leu mutation of transforming growth factor induced (TGFBI) gene in a four-generation Chinese pedigree.MethodsSubjects including eight patients and seven unaffected family members received slit-lamp biomicroscopy and photography. DNA was obtained from all subjects, and exons 4 and 11 to 14 of TGFBI gene were analyzed by polymerase chain reaction and the products were sequenced. Anterior segment optical coherence tomography (AS OCT) and in vivo confocal microscopy were conducted for ten eyes of five patients. Based on the results of AS OCT and in vivo confocal microscopy, deep anterior lamellar keratoplasty (DLKP) using cryopreserved donor cornea was applied for four eyes of four patients. Four lamellar dystrophic corneal buttons were studied by light and transmission electron microscopy, and TGFBI immunohistochemistry.ResultsEight patients had typical clinical manifestations of RBCD presenting recurrent painful corneal erosion starting in their early first decades, along with age-dependent progressive geographic corneal opacities. TGFBI sequencing revealed a heterozygous mutation, Arg124Leu in all eight patients. Anterior segment optical coherence tomography and in vivo confocal microscopy showed the dystrophic deposits involved not only in subepithelial and superficial stroma, but also in mid- or posterior stroma in four examined advanced eyes. Light microscopy showed Bowman's layer was absent, replaced by abnormal deposits stain bright red with Masson's trichrome. In superficial cornea, the deposits stacked and produced three to five continuous bands parallel to the corneal collagen lamellae. In mid- to posterior stroma, numerous granular or dot- like aggregates were heavily scattered, and most of them presented around the nuclei of stromal keratocytes. Transmission electron microscopy revealed the multiple electron-dense rod-shaped deposits aggregated and formed a characteristic pattern of three to five continuous bands in superficial cornea, which were similar to those seen under light microscopy. In mid- to posterior stroma, clusters of rod-shaped bodies were scattered extracellular or intracellular of the stromal keratocytes between the stromal lamellae suggesting the close relationship between mutated proteins and keratocyte.ConclusionsThe study offer evidences indicating DLKP is a viable treatment option for advanced RBCD to avoid recurrence, and the mutated TGFBIp in dystrophic corneas are of keratocytes origin.

Dataset Information

Clinical and Ultrastructural Studies of Gelatinous Drop-Like Corneal Dystrophy (GDLD) of a Patient with TACSTD2 Gene Mutation.

Publications

Clinical and Ultrastructural Studies of Gelatinous Drop-Like Corneal Dystrophy (GDLD) of a Patient with <i>TACSTD</i>2 Gene Mutation.

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