Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair

Taketani, Yuji; Kitamoto, Kohdai; Sakisaka, Toshihiro; Kimakura, Mikiko; Toyono, Tetsuya; Yamagami, Satoru; Amano, Shiro; Kuroda, Masahiko; Moore, Tara; Usui, Tomohiro; Ouchi, Yasuo

doi:10.1038/s41598-017-16308-2

Cited by 31 publications

(19 citation statements)

References 34 publications

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“…Recently, gene therapy has developed new insights into the treatment of several genetic diseases [36]. In vitro , decreasing mutant TGFBIp expression with an allele-specific nature siRNA and correcting mutant DNA in TGFBI -mutant cells with site-specific genome editing technologies seem to provide promising approaches for TGFBI -linked CDs [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

Qin

Yuan

Cao

et al. 2019

Journal of Ophthalmology

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Background/Aims. Corneal dystrophies (CDs) belong to a group of hereditary heterogeneous corneal diseases which result in visual impairment due to the progressive accumulation of deposits in different corneal layers. So far, mutations in several genes have been responsible for various CDs. The purpose of this study is to identify gene mutations in a three-generation Hui-Chinese family associated with granular corneal dystrophy type I (GCD1). Methods. A three-generation Hui-Chinese pedigree with GCD1 was recruited for this study. Slit-lamp biomicroscopy, optical coherence tomography, and confocal microscopy were performed to determine the clinical features of available members. Whole exome sequencing was performed on two patients to screen for potential disease-causing variants in the family. Sanger sequencing was used to test the variant in the family members. Results. Clinical examinations demonstrated bilaterally abundant multiple grayish-white opacities in the basal epithelial and superficial stroma layers of corneas of the two patients. Whole exome sequencing revealed that a heterozygous missense mutation (c.1663C > T, p.Arg555Trp) in the transforming growth factor beta-induced gene (TGFBI) was shared by the two patients, and it cosegregated with this disease in the family confirmed by Sanger sequencing. Conclusions. The results suggested that the heterozygous TGFBI c.1663C > T (p.Arg555Trp) mutation was responsible for GCD1 in the Hui-Chinese family, which should be of great help in genetic counseling for this family.

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Section: Discussionmentioning

confidence: 99%

Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

Qin

Yuan

Cao

et al. 2019

Journal of Ophthalmology

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“… 32 reported that the macroscopic, microscopic, and ultrastructural appearance of TGFBI -null mouse cornea remain unaffected, suggesting that partial or complete knockdown of TGFBI could be a potential therapy against TGFBI -linked corneal dystrophies. Currently, correction of p.(Arg124His) mutation in cornea by knocking out the mutated allele is being attempted for the treatment of GCD2 33 , 34 . Our present data indicate that the knockout of the allele should be very precise during gene therapy, in case of the heterozygote, such that only the allele containing p.(Arg124His) mutation is treated, leaving the normal-sequence allele intact.…”

Section: Discussionmentioning

confidence: 99%

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

Jun

Choi

et al. 2021

Sci Rep

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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.

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“…Recently, CRISPR-Cas9-mediated genome editing for the correction of a TGFBI mutation in GCD patient-derived primary corneal keratocytes was reported [7]. Gene therapy for heredity corneal diseases may be possible in the future, it is important to accurately assess renal symptoms.…”

Section: Discussionmentioning

confidence: 99%

TGFBI-associated corneal dystrophy and nephropathy: a novel syndrome?

et al. 2018

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Transforming growth factor beta-induced (TGFBI)-associated corneal dystrophies are a group of inherited progressive corneal diseases. One of these TGFBI-associated corneal dystrophies is Avellino corneal dystrophy, an autosomal dominant corneal dystrophy characterized by multiple asymmetric stromal opacities that potentially impair vision. Recently, a case with corneal dystrophy complicated by nephropathy possessing a pathogenic variant of the TGFBI gene was reported for the first time. Here, we report the second case with the same condition and the same mutation in the TGFBI gene. The patient was an 18-year-old male. He and his father had already been diagnosed with corneal dystrophy. Proteinuria was revealed in the patient during urine screening at school. Since his serum creatinine level was raised, a percutaneous renal biopsy was performed. Light microscopy demonstrated oligomeganephronia. Electron microscopy demonstrated an irregular basement membrane. TGFBI was analyzed by direct sequencing. A heterozygous mutation c.371G > A in exon 4, which caused an amino acid substitution from arginine to histidine at codon 124, was identified in the patient and his father. Although only one case of TGFBI-associated corneal dystrophy and nephropathy has been reported, our case's clinical and pathological findings were almost identical to those in that reported case. Further investigations of this new disease entity should be reported to all nephrologists and ophthalmologists.

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Repair of the TGFBI gene in human corneal keratocytes derived from a granular corneal dystrophy patient via CRISPR/Cas9-induced homology-directed repair

Cited by 31 publications

References 34 publications

Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

Identification of a Heterozygous Mutation in the TGFBI Gene in a Hui-Chinese Family with Corneal Dystrophy

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

TGFBI-associated corneal dystrophy and nephropathy: a novel syndrome?

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