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Related Experiment Videos

A trabecular meshwork glucocorticoid response (TIGR) gene mutation affects translocational processing.

C C Zimmerman1, V R Lingappa, J E Richards

  • 1Cellular Pharmacology Laboratory, Department of Ophthalmology, University of California San Francisco, San Francisco, CA 94143-0730, USA. drcarin@itsa.ucsf.edu

Molecular Vision
|August 25, 1999
PubMed
Summary

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The E323K mutation in the trabecular meshwork glucocorticoid response (TIGR) gene significantly alters protein processing, suggesting a unique glaucoma pathogenesis. This finding aids in understanding early-onset open-angle glaucoma.

Area of Science:

  • Molecular Biology
  • Ophthalmology
  • Genetics

Background:

  • The trabecular meshwork glucocorticoid response (TIGR) gene, also known as myocilin (MYOC), is implicated in glaucoma.
  • The E323K mutation in MYOC is strongly associated with early-onset open-angle glaucoma, despite minimal predicted structural impact.

Purpose of the Study:

  • To investigate the functional consequences of the E323K mutation in MYOC on protein processing through the endoplasmic reticulum (ER).
  • To compare the effects of E323K with other MYOC mutations with known structural impacts and glaucoma associations.

Main Methods:

  • Utilized an established assay for ER translocation function with normal and mutant MYOC cDNA constructs.
  • Defined "paused" regions in protein translocation via proteinase K sensitivity and assessed the ability to restart translocation with EDTA.

Related Experiment Videos

  • Evaluated the E323K mutation and adjacent mutations (G246R, G364V, P370L).

    • Main Results:

    • Native MYOC exhibits a translocational pause in a region of high olfactomedin (OLF) homology.
    • The E323K mutation markedly disrupted the normal protein pausing pattern, introducing a new or enhanced band approximately 3 kDa higher.
    • Other examined MYOC mutants did not produce this specific effect.

    Conclusions:

    • The major translocational pause in MYOC may explain mutation hotspots associated with glaucoma.
    • The E323K mutation appears to delay normal TIGR biogenesis pausing.
    • This suggests a distinct pathogenic mechanism for E323K compared to other MYOC mutations.