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Compound heterozygous mutations in TGFBI cause a severe phenotype of granular corneal dystrophy type 2.

ABSTRACT: We investigated the clinical and genetic features of patients with severe phenotype of granular corneal dystrophy type 2 (GCD2) associated with compound heterozygosity in the transforming growth factor-β-induced (TGFBI) gene. Patients with severe GCD2 underwent ophthalmic examination (best-corrected visual acuity test, intraocular pressure measurement, slit-lamp examination, and slit-lamp photograph analysis) and direct Sanger sequencing of whole-TGFBI. The patient's family was tested to determine the pedigrees. Five novel mutations (p.(His174Asp), p.(Ile247Asn), p.(Tyr88Cys), p.(Arg257Pro), and p.(Tyr468*)) and two known mutations (p.(Asn544Ser) and p.(Arg179*)) in TGFBI were identified, along with p.(Arg124His), in the patients. Trans-phase of TGFBI second mutations was confirmed by pedigree analysis. Multiple, extensive discoid granular, and increased linear deposits were observed in the probands carrying p.(Arg124His) and other nonsense mutations. Some patients who had undergone phototherapeutic keratectomy experienced rapid recurrence (p.(Ile247Asn) and p.(Asn544Ser)); however, the cornea was well-maintained in a patient who underwent deep anterior lamellar keratoplasty (p.(Ile247Asn)). Thus, compound heterozygosity of TGFBI is associated with the phenotypic variability of TGFBI corneal dystrophies, suggesting that identifying TGFBI second mutations may be vital in patients with extraordinarily severe phenotypes. Our findings indicate the necessity for a more precise observation of genotype-phenotype correlation and additional care when treating TGFBI corneal dystrophies.

SUBMITTER: Jun I

PROVIDER: S-EPMC7997986 | biostudies-literature |

REPOSITORIES: biostudies-literature

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The TGFBI R555W mutation induces a new granular corneal dystrophy type I phenotype.

Project description:PurposeTo report the clinical and molecular features of a distinct form of transforming growth factor-β-induced (TGFBI) gene-linked corneal dystrophy exhibiting a new granular corneal dystrophy type I (CDGG1) phenotype.MethodsA complete ophthalmologic examination was performed in all individuals of a Chinese family in which autosomal dominant transmission of the disease had been observed. DNA was obtained from the peripheral blood leukocytes of each participating subject. Genetic analyses included keratin 3 (KRT3), keratin 12 (KRT12), and TGFBI polymerase chain reaction (PCR) amplification and automated nucleotide sequencing of exons from the genomic DNA.ResultsThe corneal phenotype in this pedigree was characterized by multiple bilateral dot-like, circular opacities at different corneal depths, with some of the affected individuals only having opacities in the epithelium, which is different from the typical CDGG1 phenotype. TGFBI analysis revealed a heterozygous point mutation at exon 12 (c.1663C>T) in all of the affected individuals, predicting a p.R555W missense mutation.ConclusionsThe phenotype which resulted from the TGFBI R555W mutation in this family is distinct from that observed in the typical case of CDGG1. We propose this disorder should be classified as a new phenotype of CDGG1, and this finding demonstrates the importance of gene diagnosis in the corneal dystrophies.

| S-EPMC3025098 | biostudies-literature

A unique TGFBI protein in granular corneal dystrophy types 1 and 2.

Project description:Types 1 and 2 granular corneal dystrophies (GCD) are primarily associated with accumulation of the R555W and R124H mutant transforming growth factor β-inducible proteins (TGFBIp) in corneal stroma, respectively. However, specific components of TGFBIp responsible for granular deposits have not been delineated. This study was undertaken to identify the mutant TGFBIp components potentially responsible for GCD.Recombinant TGFBIp of wild-type (WT) and three mutants, R124C, R124H, and R555W, were generated in HEK293FT cells. WT and TGFBIp mutants were collected from cell lysates. Immunoblot analyses were performed with five different antibodies directed against various regions of WT TGFBIp.WT and TGFBIp mutants showed differential reactivities with these antibodies. In contrast to our prior observation in purified WT and TGFBIp mutants, TGFBIp from cell lysates were less prone to polymerize. A unique 35 kD fragment was detected in cell lysates of R555W and R124H, but not in those of WT or R124C, by a commercial antibody raised against amino acids (a.a.) 199-406 of TGFBIp.Monomeric and polymeric WT and TGFBIp mutants were observed in vitro. The 35 kD fragment found only in R555W and R124H, but not in WT and R124C cell lysates, is likely a degraded TGFBIp derived from the central domain of these mutants and this fragment may be contributory to the nonamyloid granular deposits observed in GCD 1 and 2.

| S-EPMC5552038 | biostudies-other

Novel compound heterozygous mutations in the <i>CHST6</i> gene cause macular corneal dystrophy in a Han Chinese family.

Project description:BackgroundMacular corneal dystrophy (MCD), a rare autosomal recessive disorder, is caused by pathogenic mutations in the carbohydrate sulfotransferase 6 gene (CHST6) and is characterized by bilateral progressive stromal clouding and vision loss. Corneal transplantation is often necessary. This study aimed to identify disease-causing mutations in a Han-Chinese MCD patient.MethodsA 37-year-old female diagnosed with MCD was recruited. The clinical materials were observed and described, and peripheral blood sample was extracted. Whole exome sequencing (WES) and Sanger sequencing were used to reveal genetic defects. The pathogenicity of identified mutations was assessed using in silico analysis.ResultsThe patient had typical features of MCD, including decreased vision, multiple irregular gray-white corneal opacities, and corneal thinning. A novel nonsense mutation c.544C>T (p.Gln182Ter) and a validated missense mutation c.631C>G (p.Arg211Gly) were identified in the CHST6 gene coding region, both classified as "pathogenic" following the American College of Medical Genetics and Genomics standards and guidelines.ConclusionsThis study reports a Han-Chinese MCD patient with a novel nonsense mutation c.544C>T (p.Gln182Ter) and a recurrent missense mutation c.631C>G (p.Arg211Gly), which expand the spectrum of genetic mutations. The results of this study extend genotype-phenotype correlations between the CHST6 gene mutations and MCD clinical findings, contributing to a more accurate diagnosis and the development of potential gene-targeted MCD therapies.KeywordsCarbohydrate sulfotransferase 6 gene (CHST6); compound heterozygous mutations; Han Chinese family; macular corneal dystrophy (MCD).

| S-EPMC8106006 | biostudies-literature

Vortex Pattern of Corneal Deposits in Granular Corneal Dystrophy Associated With the p.(Arg555Trp) Mutation in TGFBI.

Project description:To describe 2 unrelated families with multiple members demonstrating a less commonly recognized vortex pattern of corneal deposits confirmed to be granular corneal dystrophy type 1 (GCD1) after identification of the p.(Arg555Trp) mutation in the transforming growth factor ?-induced gene (TGFBI).A slit-lamp examination was performed on individuals from 2 families, one of Mexican descent and a second of Italian descent. After DNA extraction from affected individuals and their unaffected relatives, TGFBI screening was performed.Eight of 20 individuals in the Mexican family and 20 of 55 in the Italian family demonstrated corneal stromal opacities. Seven of the 8 affected individuals in the Mexican family and 4 of the 20 affected individuals in the Italian family demonstrated a phenotype characterized by a "sea fan" or vortex pattern of superficial stromal corneal deposits originating from the inferior aspect of the cornea. Screening of TGFBI in both families revealed a heterozygous missense mutation [p.(Arg555Trp)] in exon 12, confirming the diagnosis of GCD1.Our findings demonstrate that GCD1 may present with a vortex pattern of anterior stromal deposits. Although this pattern of dystrophic deposits is not recognized by clinicians as a typical phenotype of GCD1, it is consistent with the production of the majority of the TGFBI protein by the corneal epithelium.

| S-EPMC5298206 | biostudies-literature

TGFBI gene mutations in a Korean population with corneal dystrophy.

Project description:PURPOSE: To investigate the clinical and genetic features of Korean patients with corneal dystrophies associated with mutations in the human transforming growth factor-?-induced (TGFBI) gene. METHODS: In this study, 387 subjects (71 families and 89 individuals - 268 patients having TGFBI corneal dystrophies and 119 normal relatives) were assessed. All subjects underwent a complete ophthalmologic evaluation, including biomicroscopic inspection and dilated fundus examination. As a control, 100 individuals without corneal disease were selected from the general population. The polymerase chain reaction (PCR) and direct sequencing were used to screen for mutations in TGFBI. RESULTS: All subjects recruited exhibited a range of corneal dystrophies, including Thiel-Behnke corneal dystrophy (TBCD, R555Q; 6 families and 4 individuals), granular corneal dystrophy type 2 (GCD2, R124H; 61 families and 80 individuals), lattice corneal dystrophy (LCD; 4 families and 5 individuals; 7 with type 1 [R124C], and 2 with a variant [L527R, P542R]). The disease showed an autosomal dominant inheritance pattern in all families. CONCLUSIONS: R124H in GCD2 was the most common mutation. GCD1 and Reis-Bucklers corneal dystrophy were not found. In the GCD2 patients there were a large number of laser refractive surgery-induced corneal opacities. A spontaneous R124H mutation was confirmed in an already mutated allele that resulted in a change from a heterozygous into a homozygous form. Also, a novel mutation, P527R, was identified in LCD.

| S-EPMC3413419 | biostudies-literature

Reduced penetrance in familial Avellino corneal dystrophy associated with TGFBI mutations.

Project description:PurposeTo characterize the clinical phenotype, histopathological features, and molecular genetic basis of an Avellino corneal dystrophy (ACD) in a Chinese family.MethodsA complete ophthalmologic examination was performed in 21 individuals (6 affected and 15 unaffected) of the four-generation family. DNA was obtained from peripheral blood leukocytes of each participant. Genetic analysis included TGFBI polymerase chain reaction (PCR) amplification and automated nucleotidic sequenceing of all 17 exons of genomic DNA. Histological analysis of corneal tissue from the proband was performed after a penetrating keratoplasty. One hundred Chinese controls were scanned for the presence of the R124H mutation by amplifying TGFBI exon 4 and then by direct sequencing of PCR products.ResultsThe proband of the pedigree had phenotypic features consistent with diagnosis of ACD. He was homozygous for the same R124H mutation in TGFBI as previously reported in Japan and European countries. In addition, 4 affected and 7 unaffected individuals carried the same variation in the heterozygous state were identified. None of the 100 control subjects was positive for this mutation. Moreover, a variable expressivity and an apparent non-penetrance were observed in the individuals with heterozygous R124H mutation in our pedigree. After excluding the missed diagnosis or a late onset, it could be interpreted as a reduced penetrance.ConclusionsWe reported a novel ACD family which exhibited a reduced penetrance of phenotype in northern China. This outcome supports that although the R124H mutation is one of the genetic causes of the disease, different genetic and environmental factors may influence the expressivity and the penetrance. Uncovering the mechanism may facilitate us to inhibit the occurrence of the corneal dystrophy caused by the R124H mutation in TGFBI, irrespective of the homozygous and heterozygous mutation.

| S-EPMC2622714 | biostudies-literature

Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening.

Project description:STIL (SCL/TAL1 interrupting locus) is a core component of the centriole duplication process. STIL mutations have been associated with both autosomal recessive primary microcephaly (MCPH) and holoprosencephaly. In this report, we describe a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum. Whole exome sequencing allowed us to identify novel compound heterozygous mutations in STIL. The mutations lie, respectively, in the CPAP/CENPJ and the hsSAS6 interacting domains of STIL. M-phase synchronized amniocytes from both affected fetuses did not display an aberrant number of centrioles, as shown previously for either STIL-depleted or overexpressing cells. However, we observed an elongation of at least 1 centriole for each duplicated centrosome. These preliminary results may point to a novel mechanism causing MCPH and embryonic lethality in humans.

| S-EPMC5701267 | biostudies-literature

Genotype-phenotype correlations in Chinese patients with TGFBI gene-linked corneal dystrophy.

Project description:In this paper, we report the clinical and molecular features of the distinct TGFBI (human transforming growth factor β-induced, OMIM No. 601692) gene-linked corneal dystrophy. Altogether, five pedigrees and ten unrelated individuals diagnosed as corneal dystrophy were recruited. Peripheral venous DNA was extracted, and then amplified by polymerase chain reaction (PCR) and scanned for mutation by single-stranded conformation polymorphism (SSCP). Direct DNA sequencing was used to analyze the mutations of the TGFBI gene. In our study, thirty patients from five pedigrees and ten sporadic patients were diagnosed as four TGFBI gene-linked corneal dystrophies of granular corneal dystrophy type I (GGCD I), Avellino corneal dystrophy (ACD), lattice corneal dystrophy type I (LCD I), and lattice corneal dystrophy type IIIA (LCD IIIA), and in total, seven disease-causing mutations, namely R555W, A546D, A546T, and T538P mutations in exon 12, R124H and R124C mutations in exon 4, and P501T mutation in exon 11, were identified, while four polymorphisms of V327V, L472L, F540F, and 1665-1666insC were screened in exons 8, 11, and 12. The study ascertained the tight genotype-phenotype relationship and confirmed the clinical and genetic features of four TGFBI gene-linked corneal dystrophies.

| S-EPMC3072592 | biostudies-literature

Investigation of TGFBI (transforming growth factor beta-induced) Gene Mutations in Families with Granular Corneal Dystrophy Type 1 in the Konya Region.

Project description:Objectives:Granular corneal dystrophies (GCD) are characterized by small, discrete, sharp-edged, grayish-white opacities in the corneal stroma. Among the genes responsible for the development of GCD, the most strongly related gene is transforming growth factor beta-induced (TGFBI), located in the 5q31.1 locus. Studies show that R124H in exon 4 and R555W in exon 12 are hot-spot mutations in the TGFBI gene that lead to GCD development. In this study, we aimed to investigate these two hot-spot mutations in exons 4 and 12 of the TGFBI gene and other possible mutations in the same regions, which code important functional regions of the protein, in Turkish families with GCD and to determine the relationship between the mutations and disease and related phenotypes. Materials and Methods:The study included 16 individuals diagnosed with GCD type 1 (GCD1), 11 of these patients' healthy relatives, and 28 unrelated healthy individuals. DNA was obtained from peripheral blood samples taken from each individual and polymerase chain reaction was used to amplify target gene regions. Genotyping studies were done by sequence analysis. Results:The R124S mutation in exon 4 of TGFBI was not detected in the patients or healthy individuals in our study. However, all individuals diagnosed as having GCD1 were found to be heterozygous carriers of the R555W mutation in exon 12 of TGFBI. This mutation was not detected in healthy family members or control individuals unrelated to these families. In addition, we detected the silent mutation F540F in exon 12 and c.32924 G>A substitution in an intronic region of the gene in a few patients and healthy individuals. Conclusion:Our study strongly supports the association of GCD1 with R555W mutation in exon 12 region of the TGFBI gene, as reported in the literature.

| S-EPMC7204905 | biostudies-literature

Chinese family with atypical granular corneal dystrophy type I caused by the typical R555W mutation in TGFBI.

Project description:AIM:To investigate the clinical features and genetic defects in four generations of a Chinese family affected with atypical granular corneal dystrophy type I (GCD type I). METHODS:Family history and clinical data were recorded. Genomic DNA samples were obtained from peripheral blood leukocytes of all participated. Exons of the transforming growth factor-?-induced (TGFBI) gene were directly sequenced after being amplified by polymerase chain reaction (PCR), and multi-point linkage analysis using microsatellite makers flanking the gene was applied to identify the disease-causing mutation. RESULTS:Clinical features were quite variable in patients, some patients only had opacities in the epithelium, and others revealed multiple bilateral circular, discrete, crumb-like opacities mainly in the epithelium, with several in different depths of corneal stroma, and the performance was different bilaterally, even in the same patient. Directly nucleotide sequencing revealed a heterozygous p.R555W mutation in the coding sequence of the TGFBI gene in all affected individuals of the family, but was not found in all unaffected. The maximum logarithm of odds (LOD) score obtained by multi-point analysis was detected at marker locus D5S393 (LOD=2.740; ?=1.000). CONCLUSION:Our case presented with clinical futures and the pathogenic mutations in TGFBI gene, the phenotype of the pedigree was quite different from typical GCD type I, so we suggested that this phenotype was a variant of GCD type I. These findings expand the knowledge about GCD type I, and demonstrate that molecular genetic analysis is important to make an accurate diagnosis of patients with variable corneal dystrophies in clinic.

| S-EPMC3755303 | biostudies-literature

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