Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Zhou, Tiger; Souzeau, Emmanuelle; Siggs, Owen M.; Landers, John; Mills, Richard A.; Goldberg, Ivan; Healey, Paul R.; Graham, Stuart L.; Hewitt, Alex W.; Mackey, David A.; Galanopoulos, Anna; Casson, Robert J.; Ruddle, Jonathan B; Ellis, Jonathan; Leo, Paul; Brown, Matthew A.; MacGregor, Stuart; Sharma, Shilpi; Burdon, Kathryn P.; Craig, Jamie E

doi:10.1167/iovs.16-21049

Cited by 12 publications

(12 citation statements)

References 53 publications

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“…The Myocilin protein is encoded by the MYOC gene and is expressed widely in the body, including in skeletal muscle, heart, lung, pancreas, corpus ciliare, trabecular meshwork, and retina [15]. Current international work holds the MYOC mutation rate to be approximately 2-6% in POAG patients [5,16]. The MYOC Y437H mutation is located in the third exon of MYOC and was first reported in 1998 [17].…”

Section: Discussionmentioning

confidence: 99%

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Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Yang

Abdulatef

Zhang³

et al. 2020

Int. J. Med. Sci.

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Objective: To identify the interaction between the MYOC Y437H mutation and TGF-β2 in a family with primary open-angle glaucoma (POAG). Methods: The MYOC Y437H mutation was identified in a family with POAG; the family was a fourth-generation family with 27 members, of which 6 members were affected. Analysis focused on the secreted myocilin protein and TGF-β2 found in the aqueous humor. Samples were taken both from normal controls and MYOC mutant carriers and cross-talk between MYOC Y437H and TGF-β2 were evaluated in the trabecular meshwork (TM) cells. Results: Aqueous humor secreted myocilin protein levels were reduced while TGF-β2 levels were increased in patients with the MYOC (c.1309T>C) mutation. This inverse relationship indicated that elevated TGF-β2 may be an important pathogenic mechanism in the progression of myocilin-related POAG. In TM cells expressing the MYOC Y437H mutant, exogenous TGF-β2 also significantly increased myocilin expression as well as the endoplasmic reticulum (ER) stress markers GRP94 and CHOP. This increase in TGF-β2 was also associated with increased cell death in cells carrying the MYOC Y437H mutation. Conclusion: These data collectively suggest that the mutual interaction between glaucomatous MYOC mutation and TGF-β2 contributed to the cell death of TM cells. This relationship also provides a new, therapeutic targets for the treatment of glaucoma.

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Section: Discussionmentioning

confidence: 99%

“…Important risk factors for POAG include genetics, age, and environment. Previous reports have shown that gene mutations in MYOC, OPTN, and WDR36 are associated with the incidence of POAG [3][4][5]. Recently, we studied a large family from Hunan in China that had several members suffering from POAG.…”

Section: Introductionmentioning

confidence: 99%

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Yang

Abdulatef

Zhang³

et al. 2020

Int. J. Med. Sci.

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“…JOAG is inherited mainly as a dominant trait with an onset age ranging from 3 to 35 years and characterized by high IOP requiring in most of the cases early surgical treatment. The major genetic players are mutations in MYOC with high prevalence and penetrance, followed by OPTN (optineurin) and WDR36 (WD repeat containing protein 36) ( 11 ). Aniridia is a very rare panocular disease whereby glaucoma is diagnosed in 50–70% of the cases at later ages (end of adolescent, early adulthood).…”

Section: Introductionmentioning

confidence: 99%

A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations

Khalil

Al‐Haddad

Hariri

et al. 2017

Front. Cardiovasc. Med.

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Congenital heart diseases (CHDs) are still the leading cause of death in neonates. Anterior segment dysgenesis is a broad clinical phenotype that affects the normal development of the eye, leading in most of the cases to glaucoma which is still a major cause of blindness for children and adolescents. Despite tremendous insights gained from genetic studies, a clear genotype–phenotype correlation is still difficult to draw. In Lebanon, a small country with still a high rate of consanguineous marriages, there are little data on the epidemiology of glaucoma amongst children with or without CHD. We carried out whole exome sequencing (WES) on a family with anterior segment dysgenesis, and CHD composed of three affected children with glaucoma, two of them with structural cardiac defects and three healthy siblings. The results unravel a novel mutation in FOXC1 (p. R127H) segregating with the phenotype and inherited from the mother, who did not develop glaucoma. We propose a digenic model for glaucoma in this family by combining the FOXC1 variant with a missense variant inherited from the father in the dermatopontin (DPT) gene. We also unravel a novel NFATC1 missense mutation predicted to be deleterious and present only in the patient with a severe ocular and cardiac phenotype. This is the first report on FOXC1 using WES to genetically characterize a family with both ocular and cardiac malformations. Our results support the usage of such technology to have a better genotype–phenotype picture for Mendelian-inherited diseases for which expressivity and penetrance are still not answered.

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“…Five genes that cause POAG ( MYOC , OPTN , WDR36 , NTF4 , and TBK1 ) have been identified, but mutations in these genes cause disease in less than 10% of cases with POAG. [ 5 6 ] The combined effect of several genes and gene-environment interactions is expected to be important in the etiology of POAG in patients without mutations in the above-mentioned genes. [ 7 ] Genome-wide association studies and genetic studies of traits relevant to glaucoma, such as central cornea thickness, are useful for identifying genes that contribute to glaucoma in a non-Mendelian fashion.…”

Section: Introductionmentioning

confidence: 99%

FMNL2 with functions related to the cytoskeleton is partially regulated by PAX6

Ghorbanpour

Pasalar

Yazdani

et al. 2017

J Ophthalmic Vis Res

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Purpose:We aimed to assess whether the transcription factor PAX6 affects transcription of FMNL2. PAX6 is a transcription factor with significant roles in development of the eye and eye-related functions. FMNL2 encodes a member of the formin family of proteins and has roles in polymerization of actin and features of the cytoskeleton. The state of the cytoskeleton affects the flow of aqueous humor, disruption of which is a cornerstone of glaucoma pathology.Methods:Initially, bioinformatics were used extensively to identify FMNL2 as an appropriate candidate gene for possible targeting by PAX6. Subsequently, direct targeting of the promoter of FMNL2 by PAX6 was tested using the dual luciferase assay. The experiment was performed by cloning a promoter region of FMNL2 that contains PAX6 binding sitesupstream of a firefly luciferase gene and comparison of expression of luciferase in the presence and absence of PAX6 expression vectors in the HEK293T cell line. The effect of PAX6 on endogenous expression of FMNL2 in primary trabecular meshwork (TM) cells was assessed by real-time polymerase chain reaction.Results:Dual luciferase assays in HEK293T cells clearly demonstrated that PAX6 directly affects the FMNL2 promoter to increase expression of downstream sequences. However, overexpression of PAX6 in TM cells caused mild but statistically significant downregulation of endogenous FMNL2 as assessed by real-time polymerase chain reaction.Conclusion:It is concluded that PAX6 can indeed directly affect transcription of FMNL2. However, regulation of FMNL2 expression in TM cells is complicated and not limited to the direct effects of PAX6.

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Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Cited by 12 publications

References 53 publications

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

Cross-talk between MYOC p. Y437H mutation and TGF-β2 in the pathology of glaucoma

A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations

FMNL2 with functions related to the cytoskeleton is partially regulated by PAX6

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