Recurrent Myocilin Asn480Lys Glaucoma Causative Mutation Arises De Novo in a Family of Andean Descent

Guevara‐Fujita, Maria Luisa; Perez-Grossmann, Rodolfo A.; Estrada-Cuzcano, Alejandro; Pawar, Hemant; Vargas, Enrique; Richards, Julia E.; Fujita, Ricardo

doi:10.1097/ijg.0b013e318133fc5b

Cited by 8 publications

(15 citation statements)

References 24 publications

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“…Diagnosis JOAG (Brézin et al, 1998; Mimivati, Nurliza, Marini, & Liza‐Sharmini, 2014; R. Rose et al, 2011) POAG (Adam et al, 1997; Brézin et al, 1998; Guevara‐Fujita et al, 2008; Hulsman et al, 2002; Melki, Belmouden, et al, 2003) …”

Section: Introductionmentioning

confidence: 99%

“…POAG (Adam et al, 1997; Brézin et al, 1998; Guevara‐Fujita et al, 2008; Hulsman et al, 2002; Melki, Belmouden, et al, 2003)…”

Section: Introductionmentioning

confidence: 99%

“…Family History of POAG/JOAG? Yes (Adam et al, 1997; Brézin et al, 1998; Guevara‐Fujita et al, 2008; Hulsman et al, 2002; Mimivati et al, 2014; R. Rose et al, 2011) …”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

“…POAG (Adam et al, 1997; Brézin et al, 1998; Guevara‐Fujita et al, 2008; Hulsman et al, 2002; Melki, Belmouden, et al, 2003)…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Tato mutace byla zjištěna i u dalších rodinných příslušníků IV:2, IV:4, IV:7, IV:9, V:3, V:5, V:6 a V:7 (Obrázek 2B). Také varianta c.1440C>A byla v souvislosti s výskytem PGOÚ opakovaně popsána [13][14][15][16]. Variantu jsme klasifikovali jako patogenní, stejně jako databáze Clinvar, kde je interpretována jako kauzální pod identifikátorem VCV000007951.1.…”

Section: Výsledkyunclassified

Primary Open-Angle Glaucoma due to Mutations in the MYOC Gene

Vergaro¹,

Rezková²,

Fichtl³

et al. 2022

CSO

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Aim: Mutations in the myocilin gene (MYOC) cause trabecular dysfunction and thus are involved in the pathogenesis of primary open-angle glaucoma (POAG). The aim of this study was to characterize and describe the clinical findings in two Czech families with POAG due to pathogenic variants in the MYOC gene. Material and methods: Members of the two families affected by POAG underwent complete ophthalmological examination. In the proband from the first family, a direct sequencing of the three most frequent mutations in the MYOC gene was performed, and in the proband from the second family, an exome sequencing was performed. Other family members underwent targeted tests using direct sequencing. Results: In total, 10 individuals diagnosed with POAG aged 20–70 years (mean 32.2 years, SD ±10.9 years) were examined. Eight of them showed advanced glaucomatous neuropathy with severe changes in the retinal nerve fiber layer. Clinical signs of POAG were present in six individuals in the third decade of life already; another four developed POAG during the fourth decade of life. Eight out of 10 patients had to undergo filtration surgery. Surgery was performed within 1 to 7 years of diagnosis, but mostly was performed within 2 years of glaucoma diagnosis. In the first family, MYOC variant c.1099G>A p.(Gly367Arg) was shown in the affected family members; in the second family MYOC variant c.1440C>A p.(Asn480Lys), both in heterozygous state. The changes were assessed as pathogenic. Conclusion: Our study is the first to describe mutations in the MYOC gene causing POAG in Czech patients. Genetic testing may be recommended for this diagnosis, especially in individuals with early presentation and a positive family history. Carriers of pathogenic variants of the MYOC gene have a lifetime risk of developing POAG of more than 50% and the course of their disease is often more aggressive, requiring surgical intervention to permanently control the intraocular pressure.

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“…The study of MYOC (OMIM #601652) (locus GLC1A ) has identified both known mutations in European and African‐American populations, as well as novel mutations. Interestingly, these variants are correlated with African ancestry (Chincha and Cañete) and the novel are recurrent in Peru, probably indicating an autochthonous founder effect (Guevara‐Fujita et al, ; Mendoza‐Reinoso et al, ). Another disease studied at CGBM‐USMP is retinitis pigmentosa—which has a genetic heterogeneity, with more than 70 genes—in approximately 100 Peruvian families, having identified the causative mutation in 30 of them.…”

Section: Basic and Translational Research On Genetics And Genomicsmentioning

confidence: 99%

Genetics and genomics in Peru: Clinical and research perspective

Guio

Poterico

Levano³

et al. 2018

Molec Gen & Gen Med

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Recurrent Myocilin Asn480Lys Glaucoma Causative Mutation Arises De Novo in a Family of Andean Descent

Cited by 8 publications

References 24 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

Primary Open-Angle Glaucoma due to Mutations in the MYOC Gene

Genetics and genomics in Peru: Clinical and research perspective

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