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.
| S-EPMC6804947 | biostudies-literature
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.
| S-EPMC2862246 | biostudies-literature
Project description:PURPOSE: To 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). METHODS: Genetic 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. RESULTS: We 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. CONCLUSIONS: The 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.
| S-EPMC2728569 | biostudies-literature
Project description:PURPOSE: To report the findings of the clinical and molecular evaluation in a Greek family with fleck corneal dystrophy (CFD). METHODS: A 58-year-old woman was seen on routine ophthalmic examination and diagnosed as having CFD. All available family members were examined to evaluate the clinical findings and inheritance of the disease. Twenty members of the family in five generations underwent slit-lamp examination. Eleven were females and nine males, aged from two years to 85 years old. Blood samples were available from four patients with CFD and seven unaffected relatives, and the DNAs were subjected to molecular screening of the phosphoinositide kinase, five finger-containing (PIKFYVE) gene by direct sequencing or denaturing high performance liquid chromatography (DHPLC). RESULTS: The clinical evaluation revealed six family members (five females and one male) with CFD. In two CFD patients early cataract formation was noticed. All patients affected with the corneal dystrophy were asymptomatic. The molecular analyses demonstrated the existence of a novel c.3060-3063delCCTT (p.P968Vfs23) mutation in PIKFYVE in all CFD patients tested but in none of the six unaffected family members. No molecular screening was performed in the seventh unaffected member as the causative mutation was clearly transmitted from his affected wife to his affected son. CONCLUSIONS: We report on the clinical and molecular findings of a five generation Greek family with CFD and we conclude that the novel c.3060-3063delCCTT (p.P968Vfs23) mutation in PIKFYVE, which segregated with the disease, was the causative mutation in this family.
| S-EPMC3209427 | biostudies-literature
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.
| S-EPMC2774463 | biostudies-literature
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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Project description: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.
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Project description:In the current study, we conducted a mutation screening of tumor-associated calcium signal transducer 2 (TACSTD2) gene in six consanguineous Iranian families with gelatinous drop-like corneal dystrophy (GDLD), in order to find the causative mutations. Detailed eye examination was performed by ophthalmologist to confirm GDLD in patients. To detect the possible mutations, direct Sanger sequencing was performed for the only exon of TACSTD2 gene, and its boundary regions in all patients. In the patients with GDLD, the corneal surface showed lesions with different shapes from mild to severe forms depending on the progress of the disease. The patients showed grayish corneal deposits as a typical mulberry form, corneal dystrophy along with corneal lipid deposition, and vascularization. Targeted Sanger sequencing in TACSTD2 gene revealed the causative mutations in this gene in all studied families. Our study expanded the mutational spectrum of TACSTD2 which along with the related symptoms could help with the diagnosis, and management of the disease.
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Project description:BACKGROUND:The molecular basis of Meesmann's epithelial corneal dystrophy (MECD) has recently been attributed to mutations in the cornea specific keratin genes KRT3 and KRT12. The mechanisms by which these mutations cause the Meesmann's phenotype are not clear. This study presents new data, examines clinical, histological, ultrastructural, and molecular aspects of MECD, and compares the features seen in this condition with those observed in other well studied keratin diseases such as epidermolysis bullosa simplex. METHODS:A two generation family with typical features of Meesmann's epithelial corneal dystrophy (MECD) was studied. All family members were examined under a slit lamp. Biopsy material from elective keratoplasty was studied by histopathological and ultrastructural analysis using standard techniques. Direct automated sequencing of genomic DNA was used for mutation detection, mutations were confirmed by restriction digest analysis. RESULTS:The abnormal corneal epithelium was acanthotic and contained numerous dyskeratotic cells and intraepithelial vesicles. By electron microscopy abnormally aggregated and clumped keratin filament bundles were detected in basal and suprabasal keratinocytes from the centre of the cornea. Direct sequencing of the patients' genomic DNA revealed a novel missense mutation (423T>G) in exon 1 of the cornea specific keratin 12 (KRT12) gene. This mutation predicts the amino acid change N133K within the helix initiation motif of the K12 polypeptide. Comparative studies with well established keratin disorders of other human epithelia underscore the pathogenic relevance of K3 and K12 gene mutations in Meesmann's epithelial corneal dystrophy. The morphological data presented here illustrate the disruptive effects of keratin gene mutations on the integrity of corneal keratinocytes. CONCLUSIONS:A clinical, histopathological, and ultrastructural study of a previously unreported family with MECD is presented. In this family the disease is ascribed to a novel mutation in KRT12. A molecular mechanism is proposed for MECD based on the comparison with other well characterised keratin diseases.
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Project description:AIM: To study a kindred with Meesmann's corneal dystrophy (MCD) to determine if a mutation within the cornea specific K3 or K12 genes is responsible for the disease phenotype. METHODS: Slit lamp examination of the cornea in four members of the kindred was carried out to confirm the diagnosis of MCD. The region encoding the helix initiation motif (HIM) of the K12 polypeptide was polymerase chain reaction (PCR) amplified from genomic DNA derived from affected individuals in the kindred. PCR products generated were subjected to direct automated sequencing. Restriction enzyme analysis employing Ban I was used to confirm the presence of the mutation in affected individuals of the family. RESULTS: Sequencing of the K12 gene in an affected individual from the family revealed a novel heterozygous missense mutation (413A-->C), predicting the substitution of a proline for a glutamine at codon 130 (Q130P) in the HIM of the K12 protein. The mutation was excluded from 50 normal, unaffected individuals by restriction enyzme analysis and was therefore unlikely to be a common polymorphism. CONCLUSION: A novel missense mutation in the K12 gene leads to MCD in a German kindred. Missense mutations have now been identified within the region encoding the helix initiation motif of the K12 protein in eight of 11 MCD kindreds analysed at the molecular level.
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