Mutation Analysis of CHST6 Gene in Chinese Patients With Macular Corneal Dystrophy

Liu, Zuguo; Tian, Xin; Iida, Nobuko; Fujiki, Keiko; Xie, Peiying; Wang, Wei; Ma, Zhizhong; Kanai, Atsushi; Murakami, Akira

doi:10.1097/ico.0b013e3181ca2e74

Cited by 8 publications

(5 citation statements)

References 19 publications

(31 reference statements)

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“…The c.631C>G (p.Arg211Gly) mutation, previously reported as unique in two other Chinese families, was identified as one of the disease-causing alleles in our patient (10,31). The identical nucleotide substitution observed in the other two families of the same ethnicity may indicate a founder effect (10,31). The c.631C>G variant leads to the arginine-to-glycine substitution, changing from a positively charged basic amino acid residue to a neutral amino acid.…”

Section: Discussionsupporting

confidence: 54%

“…Genetic mutation type and position may influence CHST6 functions, particularly conserved positions across either or both of carbohydrate sulfotransferases or within a critical domain important for enzyme activity (40). The c.631C>G (p.Arg211Gly) mutation, previously reported as unique in two other Chinese families, was identified as one of the disease-causing alleles in our patient (10,31). The identical nucleotide substitution observed in the other two families of the same ethnicity may indicate a founder effect (10,31).…”

Section: Discussionmentioning

confidence: 56%

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Novel compound heterozygous mutations in the CHST6 gene cause macular corneal dystrophy in a Han Chinese family

Huang¹,

Yuan²,

Cao³

et al. 2021

Ann Transl Med

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Background: Macular 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.Methods: A 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. Results:The patient had typical features of MCD, including decreased vision, multiple irregular graywhite 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.Conclusions: This 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.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 56%

Novel compound heterozygous mutations in the CHST6 gene cause macular corneal dystrophy in a Han Chinese family

Huang¹,

Yuan²,

Cao³

et al. 2021

Ann Transl Med

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“…2E and F). The c.803A > G variant, located in CHST6 coding exon 3 and predicted to result in a missense amino acid substitution (p.(Tyr268Cys)), is a rare variant (rs72547539; MAF 0.0002 (1000 Genome) and 0.000009 (ExAC)), that has been previously reported in four probands with MCD 9 , 10 . Measurement of serum sulfated KS and other GAG revealed decreased serum levels of all GAG compared to four aged-matched controls (Table 1).…”

Section: Case Reportmentioning

confidence: 78%

Macular corneal dystrophy with isolated peripheral Descemet membrane deposits

Zhang¹,

Kassels²,

Barrington³

et al. 2019

American Journal of Ophthalmology Case Reports

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PurposeMacular Corneal Dystrophy (MCD, MIM #217800) is a category 1 corneal stromal dystrophy as per the current IC3D classification. While characterized by macular stromal deposits, we report a case of MCD type II with isolated bilateral peripheral Decemet membrane opacities, describing the clinical features and results of screening the CHST6 gene and serum sulfated keratan sulfate levels.ObservationsA 68-year-old man with an unremarkable past medical and family history presented with bilateral progressive decrease in vision. Ocular exam revealed bilateral clear corneas with the exception of peripheral, round, gray-white discrete deposits at the level of Descemet membrane and decreased central corneal thickness in both eyes. The morphology of the corneal deposits, decreased corneal thickness and the absence of a family history were consistent with MCD, prompting screening of the CHST6 gene. Sanger sequencing followed by allele specific cloning revealed compound heterozygous CHST6 mutations in trans configuration: c.-26C > A, which created a new upstream open reading frame (uORF’), predicted to attenuate translation efficiency of the downstream main ORF; and c.803A > G (p.(Tyr268Cys)), previously associated with MCD. Serum keratan sulfate was reduced but detectable, consistent with the diagnosis of macular corneal dystrophy type II.ConclusionsAlthough macular corneal dystrophy is classified as a corneal stromal dystrophy with endothelial involvement, we report a case of MCD with dystrophic deposits confined to the peripheral Descemet membrane, indicating that MCD may be associated with isolated endothelial involvement.

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“…Ten independent mutations, seven missense, two insertions and one deletion were identified. Of these, three were novel, whereas the others were founded previously in MCD patients [ 14 ]. Furthermore, we preliminary investigated the role of ER stress and apoptosis in MCD keratocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Sulfotransferases utilize 3’-phospho-5’-adenylyl sulfate (PAPS) as a sulfonate donor to catalyze the transfer of sulfate to position 6-O of the N-acetyl-glucosamine of keratan in the cornea [ 6 , 9 – 11 ]. Mutations in C-GlcNAc6ST domains, such as the 5’PB domain, an essential part of the active site responsible for PAPS binding, seriously effect sulfotransferase activity [ 12 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

CHST6mutation screening and endoplasmatic reticulum stress in macular corneal dystrophy

Wang

Tang

et al. 2017

Oncotarget

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Macular corneal dystrophy (MCD) is an autosomal recessive disorder mainly caused by gene mutations of carbohydrate sulfotransferase (CHST6) leading to bilateral visual impairment. Because the mechanism underlying this degeneration remains poorly understood, we investigated molecular alterations and pathways that may be involved in MCD in this issue. Different mutation sites were screened by direct sequencing of the coding region of CHST6. In addition, we described morphological changes in MCD keratocytes by light microscopy and electron microscopy and determined the relationship between the development of this disease and the occurrence of apoptosis through flow cytometry, cell counting kit-8, colony formation assay and other experiments. Western blotting and quantitative real-time polymerase chain reaction were used to determine if endoplasmic reticulum (ER) stress was activated. We found 10 kinds of mutations among these families with 3 novel mutations included. The percentage of apoptotic keratocytes increased in MCD patients; furthermore, the expression of apoptosis related protein B-cell lymphoma-2 (Bcl-2) was down-regulated while Bcl-2 associated X protein was upregulated. Finally, ER stress was activated with the upregulation of glucose-regulated protein 78 and CCAAT-enhancer-binding protein homologous protein. Our clinical and in vitro results suggest that the CHST6 mutation associated with MCD is associated with apoptosis, and ER stress is probably involved in this apoptosis pathway.

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Mutation Analysis of CHST6 Gene in Chinese Patients With Macular Corneal Dystrophy

Cited by 8 publications

References 19 publications

Novel compound heterozygous mutations in the CHST6 gene cause macular corneal dystrophy in a Han Chinese family

Novel compound heterozygous mutations in the CHST6 gene cause macular corneal dystrophy in a Han Chinese family

Macular corneal dystrophy with isolated peripheral Descemet membrane deposits

CHST6mutation screening and endoplasmatic reticulum stress in macular corneal dystrophy

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