Four Novel Mutations in the PITX2 Gene in Patients with Axenfeld-Rieger Syndrome

Phillips, Jeffrey

doi:10.1159/000065602

Cited by 40 publications

(35 citation statements)

References 6 publications

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“…Among six missense sequence variants identified, PITX2 p.(Pro64Leu) has previously been reported among different families as deleterious. [23][24][25][26] The other five missense sequence variants have not been reported before and were absent from the EVS and the ExAC database. Sequence Figure 1) and predicted deleterious by Polyphen-2 and SIFT algorithms.…”

Section: Resultsmentioning

confidence: 95%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P = 0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0 ± 13.0 years) compared with PITX2 carriers (18.0 ± 10.6 years, P = 0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P = 0.03) but became comparable at 25 years old (71.4% vs 57.7%, P = 0.38). These findings have important implications for the genetic counselling of families affected by AxenfeldRieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

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Section: Resultsmentioning

confidence: 95%

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Souzeau¹,

Siggs²,

Zhou³

et al. 2017

Eur J Hum Genet

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“…Recessive mutations in CYP1B1 associate with human congenital glaucoma (Stoilov et al, 1997, Bejjani et al, 1998, Plasilova et al, 1999, Bejjani et al, 2000, Belmouden et al, 2002. Developmental malformations in some children with congenital glaucoma resemble those observed in ASD (Semina et al, 1996, Kulak et al, 1998, Doward et al, 1999, Kozlowski and Walter 2000, Priston et al, 2001, Phillips 2002. Together with the dosage sensitivity for other transcription factors (discussed above), this demonstrates the importance of a narrow range of activity of various transcription factor for normal anterior segment development and reflects a delicate balance of signaling by interacting pathways.…”

Section: Cyp1b1mentioning

confidence: 94%

Anterior segment development relevant to glaucoma

Gould¹,

Smith²,

John³

2004

Int. J. Dev. Biol.

164

121

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“…These strains are useful tools for investigating alternative mechanisms of RGC death not triggered by IOP elevation. For example, studies using EAAC1-deficient mice Genetic Phillips (2000) revealed that RGCs are more sensitive to oxidative stress in the absence of glutamate transporters (Harada et al 2007). In addition, reduced expression of these transporters can cause a buildup of glutamate in the eye.…”

Section: Animal Models Of Glaucomamentioning

confidence: 99%

The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma

Rosen

Stevens

2010

Advances in Experimental Medicine and Biology

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Glaucoma is one of the leading causes of vision loss worldwide, yet the signals that initiate the progressive degeneration of optic nerve axons and the selective loss of retinal ganglion neurons (RGCs) remain elusive. Reactive gliosis, release of inflammatory cytokines, and complement upregulation all occur in the early stages of glaucoma in several disease models. Recent work has implicated the classical complement cascade in the elimination of excess synaptic connections in the developing visual system and in early synapse loss associated with glaucoma, suggesting that mechanisms of developmental synapse elimination may be aberrantly re-activated in glaucoma. This review describes current evidence in support of this "synaptic" hypothesis and places complement in the context of other well-described mechanisms of neurodegeneration occurring in the glaucomatous eye.

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Four Novel Mutations in the PITX2 Gene in Patients with Axenfeld-Rieger Syndrome

Cited by 40 publications

References 6 publications

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Erratum: Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Anterior segment development relevant to glaucoma

The Role of the Classical Complement Cascade in Synapse Loss During Development and Glaucoma

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