Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function

Su Kim Byong Su Kim, O. V. Savinova, Mark Reedy, J. Martin, Y. Lun, L. Gan, R. S. Smith, S. I. Tomarev, S. W M John, R. L. Johnson

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function.

Original languageEnglish
Pages (from-to)7707-7713
Number of pages7
JournalMolecular and Cellular Biology
Volume21
Issue number22
DOIs
StatePublished - 2001

Fingerprint

Glaucoma
Mutation
Genes
Trabecular Meshwork
Intraocular Pressure
Glucocorticoids
trabecular meshwork-induced glucocorticoid response protein
Haploinsufficiency
Eye Diseases
Blindness
Chromosomes
Phenotype
Primary Open Angle Glaucoma

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. / Byong Su Kim, Su Kim; Savinova, O. V.; Reedy, Mark; Martin, J.; Lun, Y.; Gan, L.; Smith, R. S.; Tomarev, S. I.; John, S. W M; Johnson, R. L.

In: Molecular and Cellular Biology, Vol. 21, No. 22, 2001, p. 7707-7713.

Research output: Contribution to journalArticle

Byong Su Kim, SK, Savinova, OV, Reedy, M, Martin, J, Lun, Y, Gan, L, Smith, RS, Tomarev, SI, John, SWM & Johnson, RL 2001, 'Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function', Molecular and Cellular Biology, vol. 21, no. 22, pp. 7707-7713. https://doi.org/10.1128/MCB.21.22.7707-7713.2001
Byong Su Kim, Su Kim ; Savinova, O. V. ; Reedy, Mark ; Martin, J. ; Lun, Y. ; Gan, L. ; Smith, R. S. ; Tomarev, S. I. ; John, S. W M ; Johnson, R. L. / Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function. In: Molecular and Cellular Biology. 2001 ; Vol. 21, No. 22. pp. 7707-7713.
@article{4b729e41edae4840a420287feada8bd1,
title = "Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function",
abstract = "Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function.",
author = "{Byong Su Kim}, {Su Kim} and Savinova, {O. V.} and Mark Reedy and J. Martin and Y. Lun and L. Gan and Smith, {R. S.} and Tomarev, {S. I.} and John, {S. W M} and Johnson, {R. L.}",
year = "2001",
doi = "10.1128/MCB.21.22.7707-7713.2001",
language = "English",
volume = "21",
pages = "7707--7713",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "22",

}

TY - JOUR

T1 - Targeted disruption of the myocilin gene (Myoc) suggests that human glaucoma-causing mutations are gain of function

AU - Byong Su Kim, Su Kim

AU - Savinova, O. V.

AU - Reedy, Mark

AU - Martin, J.

AU - Lun, Y.

AU - Gan, L.

AU - Smith, R. S.

AU - Tomarev, S. I.

AU - John, S. W M

AU - Johnson, R. L.

PY - 2001

Y1 - 2001

N2 - Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function.

AB - Glaucoma is a heterogeneous eye disease and a major cause of blindness worldwide. Recently, primary open angle glaucoma (POAG)-associated mutations have been found in the trabecular meshwork inducible glucocorticoid response gene (TIGR), also known as the myocilin gene (MYOC), at the GLC1A locus on chromosome 1q21-q31. These mutations occurred in a subset of patients with juvenile- and adult-onset POAG and exhibited autosomal dominant inheritance. Ocular expression and its involvement in POAG suggest that TIGR/MYOC may have a role(s) in regulating intraocular pressure (IOP). Here, we report the generation and analysis of mice heterozygous and homozygous for a targeted null mutation in Myoc. Our study shows that Myoc mutant mice are both viable and fertile. Our in vivo findings further demonstrate that Myoc is not required for normal IOP or normal ocular morphology. The lack of a discernable phenotype in both Myoc-heterozygous and Myoc-null mice suggests that haploinsufficiency is not a critical mechanism for POAG in individuals with mutations in MYOC. Instead, disease-causing mutations in humans likely act by gain of function.

UR - http://www.scopus.com/inward/record.url?scp=0034780081&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034780081&partnerID=8YFLogxK

U2 - 10.1128/MCB.21.22.7707-7713.2001

DO - 10.1128/MCB.21.22.7707-7713.2001

M3 - Article

C2 - 11604506

AN - SCOPUS:0034780081

VL - 21

SP - 7707

EP - 7713

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 22

ER -