Genetic dissection of myocilin glaucoma

Gong, Gordon; Kosoko-Lasaki, Omofolasade; Haynatzki, Gleb; Wilson, M. Roy

doi:10.1093/hmg/ddh120

Cited by 22 publications

(21 citation statements)

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“…[24][25][26] MYOC gene mutation is believed to be the cause of primary open-angle glaucoma, and it is a risk factor for various types of glaucoma. 27,28 The MYOC gene is expressed in many tissues in the eye including the sclera, trabecular meshwork, ciliary body, and choroid. 29 As scleral thinning and axial extension are the underlying causes of myopia, the myopia-related MYOC gene was selected as a candidate gene for research.…”

Section: Ophthalmic Geneticsmentioning

confidence: 99%

Ten SNPs of PAX6,Lumican, andMYOCgenes are not associated with high myopia in Han Chinese

Dai

Liu

et al. 2012

Ophthalmic Genetics

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Section: Ophthalmic Geneticsmentioning

confidence: 99%

Ten SNPs of PAX6,Lumican, andMYOCgenes are not associated with high myopia in Han Chinese

Dai

Liu

et al. 2012

Ophthalmic Genetics

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“…The consensus predicted secondary structures are shown in the last line (h, alpha-helix; e, beta-strand). Blue, similar residues; red, conserved residues; asterisk, reported disease-causing mutation in human myocilin [49]. The alignment and predicted secondary structure were generated using PROMALS [53].…”

Section: Introductionmentioning

confidence: 99%

Biophysical Characterization of the Olfactomedin Domain of Myocilin, an Extracellular Matrix Protein Implicated in Inherited Forms of Glaucoma

Orwig

Lieberman

2011

PLoS ONE

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Myocilin is an eye protein found in the trabecular extracellular matrix (TEM), within the anatomic region that controls fluid flow. Variants of myocilin, localized to its olfactomedin (OLF) domain, have been linked to inherited forms of glaucoma, a disease associated with elevated intraocular pressure. OLF domains have also been implicated in psychiatric diseases and cancers by their involvement in signaling, neuronal growth, and development. However, molecular characterization of OLFs has been hampered by challenges in recombinant expression, a hurdle we have recently overcome for the myocilin OLF domain (myoc-OLF). Here, we report the first detailed solution biophysical characterization of myoc-OLF to gain insight into its structure and function. Myoc-OLF is stable in the presence of glycosaminoglycans, as well as in a wide pH range in buffers with functional groups reminiscent of such glycosaminoglycans. Circular dichroism (CD) reveals significant β-sheet and β-turn secondary structure. Unexpectedly, the CD signature is reminiscent of α-chymotrypsin as well as another ocular protein family, the βγ-crystallins. At neutral pH, intrinsic tryptophan fluorescence and CD melts indicate a highly cooperative transition with a melting temperature of ∼55°C. Limited proteolysis combined with mass spectrometry reveals that the compact core structural domain of OLF consists of approximately residues 238-461, which retains the single disulfide bond and is as stable as the full myoc-OLF construct. The data presented here inform new testable hypotheses for interactions with specific TEM components, and will assist in design of therapeutic agents for myocilin glaucoma.

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“…We found a previously reported mutation (T377M) in nine of 16 affected cases and in none of the controls; mutation was absent in six controls and two affected cases. Thus, we concluded that the majority of the glaucoma cases endemic to Veli Brgud village are due to a known point mutation in the MYOC gene, where tyrosine is replaced by methionine in the myocilin protein 4 5. It is estimated from the studies conducted to date that up to 20% of patients with early-onset OAG and 3–5% of patients with adult-onset OAG have defects in this gene 6…”

mentioning

confidence: 90%

“…However, before conducting the genome-wide scan, we checked whether some of the already known genetic variants are associated with the high prevalence of OAG in Veli Brgud population. As several different mutations in the MYOC gene coding for the myocilin protein were already associated with early-onset OAG in different populations, we performed a polymerase chain reaction and consequent DNA sequencing to screen the examinees for MYOC coding sequence changes 4 5. We found a previously reported mutation (T377M) in nine of 16 affected cases and in none of the controls; mutation was absent in six controls and two affected cases.…”

mentioning

confidence: 99%

High prevalence of glaucoma in Veli Brgud, Croatia, is caused by a dominantly inherited T377M mutation in the MYOC gene

Zgaga

Hayward

Vatavuk

et al. 2008

British Journal of Ophthalmology

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Genetic dissection of myocilin glaucoma

Cited by 22 publications

References 0 publications

Ten SNPs of PAX6,Lumican, andMYOCgenes are not associated with high myopia in Han Chinese

Ten SNPs of PAX6,Lumican, andMYOCgenes are not associated with high myopia in Han Chinese

Biophysical Characterization of the Olfactomedin Domain of Myocilin, an Extracellular Matrix Protein Implicated in Inherited Forms of Glaucoma

High prevalence of glaucoma in Veli Brgud, Croatia, is caused by a dominantly inherited T377M mutation in the MYOC gene

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