Novel TACSTD2 mutation in gelatinous drop-like corneal dystrophy.
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ABSTRACT:
SUBMITTER: Jongkhajornpong P
PROVIDER: S-EPMC4785563 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Publications
Novel TACSTD2 mutation in gelatinous drop-like corneal dystrophy.
Jongkhajornpong Passara P Lekhanont Kaevalin K Ueta Mayumi M Kitazawa Koji K Kawasaki Satoshi S Kinoshita Shigeru S
Human genome variation 20151126
We identified a novel mutation in the tumor-associated calcium signal transducer 2 (TACSTD2) gene in a consanguineous Thai family with gelatinous drop-like corneal dystrophy (GDLD). All affected family members presented with an intense amyloid substance deposited on the cornea, which required surgical management. Genetic analysis of these individuals revealed a homozygous mutation c.79delC, in the TACSTD2 gene. Both parents of these individuals were unaffected and showed heterozygous mutations i ...[more]
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Project description:We identified a novel mutation of the tumor-associated calcium signal transducer 2 (TACSTD2) gene in a Japanese patient with gelatinous drop-like corneal dystrophy (GDLD). Genetic analysis revealed a novel homozygous mutation (c.798delG, which may result in frameshift mutation p.Lys267SerfsTer4) in the TACSTD2 gene. This mutated gene was devoid of its original function in helping the claudin (CLDN) 1 and 7 proteins transfer from the cytoplasm to the plasma membrane.
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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.
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Project description:PurposeTo identify the molecular defect causing gelatinous drop-like corneal dystrophy (GDLD) in two Chinese brothers and report the morphological evaluation of GDLD by laser scanning confocal microscopy and Fourier-domain optical coherence tomography (OCT).MethodsGenetic analysis included polymerase chain reaction (PCR) amplification and direct nucleotide sequencing of the coding region of the tumor-associated calcium signal transducer 2 gene (TACSTD2) in DNA from the two brothers and their relatives. Laser scanning confocal microscopy and Fourier-domain OCT were performed on the left cornea of the younger brother.ResultsWe report a novel in-frame mutation of TACSTD2, c.526_576del 51, in the two brothers with GDLD. The identified molecular defect cosegregated with the disease and was not found in 50 unaffected individuals. The morphological evaluation on GDLD highlighted pathological observations at the level of epithelium and anterior stroma. The epithelial cells of GDLD cornea were irregular in shape and often elongated. Large accumulations of brightly reflective amyloid material was noted within or beneath the epithelium and within the anterior stroma.ConclusionsThe newly identified mutation expands the spectrum of mutations in TACSTD2 that may cause pathological corneal amyloidosis. Observations by in vivo confocal microscopy and Fourier-domain OCT were consistent with the histopathologic descriptions of GDLD.
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Project description:PurposeTo identify the genetic defect in the TACSTD2 gene that causes gelatinous drop-like corneal dystrophy (GDLD) in two unrelated consanguineous Chinese families.MethodsGenomic DNA was prepared from leukocytes of peripheral venous blood. The coding region of the TACSTD2 gene was evaluated by means of polymerase chain reaction and direct sequencing.ResultsSequencing of the TACSTD2 gene of the two probands revealed two novel homozygous frameshift mutations: c.84insG and c.480delC. The identified molecular defect cosegregates with the disease among affected members of the families and is not found in 50 unaffected controls.ConclusionsThis study reports two novel mutations in two GDLD families and expands the spectrum of mutations in TACSTD2 gene that may cause pathological corneal amyloidosis.
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Project description:PurposeTo report the clinicopathological findings of a Chinese patient with an unusual phenotype of gelatinous drop-like corneal dystrophy (GDLD) combined with spheroidal degeneration and to detect molecular defect in the tumor-associated calcium signal transducer 2 (TACSTD2) gene.MethodsExtensive physical and ophthalmologic examination of the patient was performed. Initially superficial keratectomy was performed for both eyes. Due to recurrence of the corneal opacity, penetrating keratoplasty for the right eye and deep lamellar keratoplasty for the left eye were performed. The obtained corneal tissues were examined by light microscopy. Molecular genetic analysis consisted of PCR amplification and direct automated sequencing of the complete coding region of TACSTD2.ResultsSlit-lamp biomicroscopy of the patient revealed bilateral band-like corneal opacities composed of brown-yellow, oily appearing droplets at the first visit. Two years after superficial keratectomy, elevated mulberry-like gelatinous lesions companied with brown-yellow droplets in the superficial cornea in both eyes were found. Histological analysis of corneal tissue revealed subepithelial amorphous deposits stained positively with Congo red, typical of GDLD. Meanwhile, eosinophilic globular deposits with irregular peripheral margins and various sizes, which were characteristics of spheroidal degeneration, were found. Sequencing of TACSTD2 from the patient revealed a novel homozygous missense mutation c.354G>C, leading to amino acid substitution Q118H in the patient.ConclusionsThis is the first report indicating a new type of gelatinous drop-like corneal dystrophy (GDLD) combined with spheroidal degeneration. Molecular analysis demonstrated a novel mutation in TACSTD2, which may expand the spectrum of mutations in TACSTD2.
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