Elliptical anterior iris stromal defects associated with PAX6 gene sequence changes

Sharan, Sapna; Mirzayans, Farideh; Footz, Tim; Walter, Michael A.; Levin, Alex V.

doi:10.1016/j.jaapos.2007.11.021

Cited by 11 publications

(4 citation statements)

References 13 publications

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“…Notably, this phenotype is associated with a specific nonsynonymous substitution that occurs within a highly conservative residue located in the PAX6 paired domain: p.(Asn114Ser). Our findings are similar to that described by Sharan et al [25]. We compared the phenotype descriptions of the two cases (Table 2).…”

Section: Discussionsupporting

confidence: 90%

An Unusual Presentation of Novel Missense Variant in PAX6 Gene: NM_000280.4:c.341A>G, p.(Asn114Ser)

Vasilyeva,

Sukhanova,

Khalanskaya

et al. 2023

CIMB

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This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the PAX6 gene’s paired domain is identified. Although this substitution is not in direct contact with DNA, its predicted stabilizing effect on the protein structure challenges the traditional understanding of PAX6 mutations, suggesting a gain-of-function mechanism. Contrary to classical loss-of-function effects, this gain-of-function hypothesis aligns with research demonstrating PAX6’s dosage sensitivity. Gain-of-function mutations, though less common, can lead to diverse phenotypes distinct from aniridia. Our findings emphasize PAX6’s multifaceted influence on ocular phenotypes and the importance of genetic variations. We contribute a new perspective on PAX6 mutations by suggesting a potential gain-of-function mechanism and showcasing the complexities of ocular development. This study sheds light on the intricate interplay of the genetic alterations and regulatory mechanisms underlying complex eye phenotypes. Further research, validation, and collaboration are crucial to unravel the nuanced interactions shaping ocular health and development.

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Section: Discussionsupporting

confidence: 90%

An Unusual Presentation of Novel Missense Variant in PAX6 Gene: NM_000280.4:c.341A>G, p.(Asn114Ser)

Vasilyeva,

Sukhanova,

Khalanskaya

et al. 2023

CIMB

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“…PAX6 disease may present with complete aniridia or with cataract, ellipsoid iris or other mild iris anomalies (33,34). Waardenburg syndrome patients may also have iris transillumination and may possibly have foveal hypoplasia and nystagmus as well; one patient in our foveal dysplasia category has Waardenburg syndrome with an MITF mutation, and foveal hypoplasia.…”

Section: Discussionmentioning

confidence: 98%

The clinical evaluation of infantile nystagmus: what to do first, and why

Bertsch¹,

Floyd²,

Kehoe³

et al. 2017

Journal of American Association for Pediatric Ophthalmology and

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“…In four families there was no intrafamilial variability relating to iris hypoplasia (18, 25, 45, and 59). Seven families (19,27,31,34,55,58 and 60) demonstrated mild intrafamilial variability (no iris abnormality to mild iris hypoplasia, or severe grades of aniridia only), and one family (42) showed more significant differences from mild grade 1 to severe grade 6 iris hypoplasia.…”

Section: Spectrum Of Iris Hypoplasia Varies With Pax6 Specific Mutation Sub-groupsmentioning

confidence: 99%

“…The spectrum of PAX6 mutations and clinical phenotypes of aniridia patients have been well described (3,7,8,(37)(38)(39)(40)(41)(42), and most studies have reported no clear genotype-phenotype correlations (8). More recent studies report cross-sectional data, but do not map disease progression.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia

Kit¹,

Cunha²,

Hagag³

et al. 2021

JCI Insight

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Aniridia is most commonly caused by haploinsufficiency of the PAX6 gene, characterised by variable iris and foveal hypoplasia, nystagmus, cataracts, glaucoma and aniridia related keratopathy (ARK). Genotype-phenotype correlations have previously been described, however detailed longitudinal studies of aniridia are less commonly reported. We identified eighty-six patients from sixty-two unrelated families with molecularly confirmed heterozygous PAX6 variants from a United Kingdom (UK)-based single-centre ocular genetics service. They were categorised into mutation groups and retrospective review of baseline to most recent clinical characteristics (ocular and systemic) were recorded. One hundred and seventy-two eyes were evaluated, with a mean follow up period of 16.3 ± 12.7 years. Nystagmus was recorded in 87.2%, and foveal hypoplasia in 75%. Cataracts were diagnosed in 70.3%, glaucoma in 20.6% and ARK in 68.6% of eyes. Prevalence, age of diagnosis and surgical intervention varied amongst mutation groups. Overall, the missense mutation sub-group had the mildest phenotype, and surgically naïve eyes maintained better visual acuity. Systemic evaluation identified type 2 diabetes in 12.8%, which is twice the UK prevalence. This is the largest longitudinal study of aniridia in the United Kingdom, providing insights into prognostic indicators for patients and guiding clinical management of both ocular and systemic features.

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Elliptical anterior iris stromal defects associated with PAX6 gene sequence changes

Cited by 11 publications

References 13 publications

An Unusual Presentation of Novel Missense Variant in PAX6 Gene: NM_000280.4:c.341A>G, p.(Asn114Ser)

An Unusual Presentation of Novel Missense Variant in PAX6 Gene: NM_000280.4:c.341A>G, p.(Asn114Ser)

The clinical evaluation of infantile nystagmus: what to do first, and why

Longitudinal genotype-phenotype analysis in 86 patients with PAX6-related aniridia

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