A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family

Yao, Yihua; Wang, Yaqin; Fang, Weifang; Zhang, Liu; Yang, Juhua; Chen, Jinyuan

doi:10.18240/ijo.2018.03.04

Cited by 7 publications

(7 citation statements)

References 20 publications

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“…Chen et al, 2011;Cobb et al, 2002;Faucher et al, 2002;Gupta et al, 2020;Iliev et al, 2008;K. G. Michels-Rautenstrauss et al, 1998;Souzeau et al, 2015;Fumiko Taniguchi et al, 2000;Vincent et al, 2002;Yao et al, 2018) • No (Gupta et al, 2020;Kanagavalli et al, 2003) gnomAD?…”

Section: Diagnosisunclassified

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

et al. 2021

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Rare variants of the olfactomedin domain of myocilin are considered causative for inherited, early-onset open-angle glaucoma, with a misfolding toxic gain-of-function pathogenic mechanism detailed by 20 years of laboratory research. Myocilin variants are documented in the scientific literature and identified through large-scale genetic sequencing projects such as those curated in the Genome Aggregation Database (gnomAD). In the absence of key clinical and laboratory information, however, the pathogenicity of any given variant is not clear, because glaucoma is a heterogeneous and prevalent age-onset disease, and common variants are likely benign. In this review, we reevaluate the likelihood of pathogenicity for the~100 nonsynonymous missense, insertion-deletion, and premature termination of myocilin olfactomedin variants documented in the literature. We integrate available clinical, laboratory cellular, biochemical and biophysical data, the olfactomedin domain structure, and population genetics data from gnomAD. Of the variants inspected,~50% can be binned based on a preponderance of data, leaving many of uncertain pathogenicity that motivate additional studies. Ultimately, the approach of combining metrics from different disciplines will likely resolve outstanding complexities regarding the role of this misfolding-prone protein within the context of a multifactorial and prevalent ocular disease, and pave the way for new precision medicine therapeutics.

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Section: Diagnosisunclassified

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

et al. 2021

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“…The three unaffected members were unable to undergo any examination. The diagnostic criteria for POAG were based on at least two of the following glaucoma characteristics, with the opening of the anterior chamber angle, excluding any secondary glaucoma: Characteristic glaucomatous changes of the optic disc, visual field defects and high IOP (>21 mmHg) ( 20 ). Ocular hypertension (OHT) was defined as IOP >22 mmHg and long-term follow-up without optic disc damage or visual field impairment ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open‑angle glaucoma

et al. 2020

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although primary open-angle glaucoma (PoaG)-related mutations in the myocilin (MYOC) gene have been reported, the underlying associations remain poorly understood. in the present study, the relationship between a MYOC mutation and PoaG was investigated using ophthalmic examination and total exon gene sequencing in a chinese family comprised of 5 individuals with PoaG and 15 unaffected individuals. Pathogenic mutations underlying PoaG were identified by whole-exome sequencing and subsequently validated by Sanger sequencing. of the family members, nine (45%) harbored heterozygous p.d208Y mutations; among these, five had POAG and four were unaffected. The mean age at diagnosis was 26.2±4.12 years and the mean intraocular pressure (ioP) was 39.7±16.58 mmHg; all affected members complained of vision loss, headaches and eye swelling. Among the five cases of PoaG, two presented with blindness. among 10 members of the family who underwent comprehensive ophthalmologic examination, 3 individuals exhibited severe visual field defects. The mean age at the time of operation was 27.2±3.54 years. in the present study, a novel MYOC mutation (c.G622T: p.d208Y) was identified that was associated with severe visual impairment, high ioP and the need for frequent surgical interventions. Some carriers of the mutation were young and did not show signs of glaucoma. These individuals should be followed-up to firmly establish whether the mutated gene is pathogenic for PoaG.

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“…Myocilin, which encodes a 504-amino acid glycoprotein and undergoes glycosylation at amino acid residues 57-59 (27), has three exons and contains two major homology regions, the N- and C-terminus (Fig. 1) (23,26,28-35). Notably, the majority of myocilin mutations are localized in exon 3 (Fig.…”

Section: Physiological Functions and Characteristics Of Myocilinmentioning

confidence: 99%

“…To date, 278 different myocilin mutations have been reported, among which pathogenic mutations account for 37.77% (26) (Fig. 1) (23,28-35), 9 of which have been identified in exon 1, 1 in exon 2, and 95 in exon 3. Myocilin predominantly displays two types of mutations: Missense mutations (83.8%), which are associated with JOAG and adult-onset POAG (16); and nonsense mutations (5.7%) (26).…”

Section: Pathogenesis Of Mutant/misfolded Myocilinsmentioning

confidence: 99%

“…Autosomal dominant disorders resulting from myocilin (28) may be caused by the following three pathogenic mechanisms: The dominant negative effect, gain of function, or haploinsufficiency (7,16). Some studies have demonstrated that neither haploinsufficiency (16,19,67,76) nor the dominant negative effect (77) are involved in myocilin-associated pathogenicity.…”

Section: Pathogenesis Of Mutant/misfolded Myocilinsmentioning

confidence: 99%

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Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

Wang

Zhang

et al. 2018

Int J Mol Med

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Myocilin is highly expressed in the trabecular meshwork (TM), which plays an important role in the regulation of intraocular pressure (IOP). Myocilin abnormalities may cause dysfunction of the TM, potentially leading to increased IOP. High IOP is a well-known primary risk factor for glaucoma. Myocilin mutations are common among glaucoma patients, and they are implicated in juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (POAG). Aggregation of aberrant mutant myocilins is closely associated with glaucoma pathogenesis. The aim of the present review was to discuss the recent findings regarding the major physiological functions of myocilin, such as intra- and extracellular proteolytic processes. We also aimed to discuss the risk factors associated with myocilin and the development of glaucoma, such as misfolded/mutant myocilin, imbalance of myocilin and extracellular proteins, and instability of mutant myocilin associated with temperature. Finally, we further outlined certain issues that are yet to be resolved, which may represent the basis for future studies on the role of myocilin in glaucoma.

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A recurrent G367R mutation in MYOC associated with juvenile open angle glaucoma in a large Chinese family

Cited by 7 publications

References 20 publications

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

Common and rare myocilin variants: Predicting glaucoma pathogenicity based on genetics, clinical, and laboratory misfolding data

Characterization of a novel mutation in the MYOC gene in a Chinese family with primary open‑angle glaucoma

Physiological function of myocilin and its role in the pathogenesis of glaucoma in the trabecular meshwork (Review)

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