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Co-localisation of advanced glycation end products and d-β-aspartic acid-containing proteins in gelatinous drop-like corneal dystrophy
  1. Yuichi Kaji1,
  2. Tetsuro Oshika1,
  3. Yutaka Takazawa2,
  4. Masashi Fukayama2,
  5. Noriko Fujii3
  1. 1Department of Ophthalmology, Tsukuba University Institute of Clinical Medicine, Ibaraki, Japan
  2. 2Department of Pathology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
  3. 3Research Reactor Institute, Kyoto University, Kumatori, Sennan, Osaka, Japan
  1. Correspondence to Dr Yuichi Kaji, Department of Ophthalmology, Tsukuba University Institute of Clinical Medicine, Tennoudai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan; kajiyuichi{at}


Purpose Gelatinous drop-like corneal dystrophy (GDLD), also known as familial subepithelial corneal amyloidosis, is an autosomal recessive disorder that causes progressive corneal opacity due to accumulation of amyloid fibrils in the corneal stroma. Genetic analyses have revealed that a mutation in membrane component chromosome 1 surface marker 1 gene is responsible for GDLD. However, the mechanism of amyloid formation in the corneal stroma remains unclear. The present study attempted to reveal the role of advanced glycation end products (AGE) and d-amino acids in amyloid formation in GDLD.

Methods Informed consent was obtained from five patients with GDLD, three patients with bullous keratopathy and three patients with interstitial keratitis and all the specimens were analysed. Localisation of amyloid fibrils was analysed using Congo-red and thioflavin T staining. In addition, the localisation of AGE (Nɛ-carboxy(methyl)-l-lysine, pyrraline and pentosidine) and d-β-aspartic acid-containing proteins, a major form of d-amino acid-containing proteins, was analysed immunohistochemically.

Results In all GDLD specimens, strong immunoreactivity to AGE and d-β-aspartic acid-containing proteins was detected in the subepithelial amyloid-rich region. In contrast, amyloid fibrils, AGE, or d-amino acid-containing proteins were slightly detected in the corneal stroma of patients with bullous keratopathy and interstitial keratitis.

Conclusions Abnormally accumulated proteins rich in AGE and d-β-aspartic acid co-localise in the amyloid lesions in GDLD. These results indicate that non-enzymatic post-translational modifications of proteins, including AGE formation and isomerisation of aspartyl residues, will be the cause as well as the result of amyloid fibril formations in GDLD.

  • Advanced glycation end products
  • biochemistry
  • cornead-amino acids
  • d-β-aspartic acid
  • familial subepithelial corneal amyloidosis
  • GDLD
  • gelatinous drop-like corneal dystrophy
  • M1S1
  • Nɛ-(carboxy)methyl-l-lysin
  • optics and refraction
  • pathology
  • pentosidine
  • physiology
  • pyrraline
  • treatment surgery
  • tumour-associated calcium signal transducer 2 (TACSTD2)

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  • Funding This work is supported by the Ministry of Education, Science, Sports and Culture, grant for scientific research 21592216 (2009–2011) and 24592618 (2012–2015), Japan.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the University of Tokyo.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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