Autosomal dominant foveal hypoplasia without visible macular abnormalities and PAX6 mutations

Matsushita, Itsuka; Morita, Hirofumi; Kondo, Hiroyuki

doi:10.1007/s10384-020-00766-9

Cited by 10 publications

(14 citation statements)

References 22 publications

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“…We studied seventeen patients from nine families (mean age 24 ± 21 years; range 1 to 68 years) and six families were diagnosed with FVH1. The findings of two of these were reported earlier [15], two families with aniridia with corneal opacities, and one family with a peripheral corneal opacity and mild iris anomaly (Table 1). The ocular examinations included measurements of the refractive error and visual acuity, and examinations using slit-lamp biomicroscopy, gonioscopy, and ophthalmoscopy.…”

Section: Clinical Examinationmentioning

confidence: 64%

“…We have recently reported our findings on two patients with PAX6 mutations associated with FVH1 [15]. Both mutations were located in loci other than the CTS, i.e., one was in the NTS and the other in the PSTD.…”

Section: Introductionmentioning

confidence: 68%

“…OCT angiography (OCTA) images were obtained from selected patients with good visual acuity, and Patient 7 who underwent examinations under general anesthesia using SS-OCT (DRI OCT Triton, Topcon, Tokyo, Japan), and Patient 13 using spectral domain OCT (RTVue XR Avanti, Optovue, Inc., Fremont, CA, USA). * Patients 1, 2, 3, and 17 have been reported in reference [15]. CTS, C-terminal subdomain; F, female; FVH1, autosomal dominant isolated foveal hypoplasia; HD, homeodomain; M, male; NA, not available; NTS, N-terminal subdomain; PD, paired domain; PSTD, proline-serine-threonine-rich domain.…”

Section: Clinical Examinationmentioning

confidence: 99%

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Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia

Matsushita

Izumi

Ueno

et al. 2023

Genes

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The human fovea is a specialized pit structure in the central retina. Foveal hypoplasia is a condition where the foveal pit does not fully develop, and it is associated with poor vision. Autosomal dominant isolated foveal hypoplasia (FVH1) is a rare condition of foveal hypoplasia (FH) that lacks any other ocular manifestations. FVH1 is associated with hypomorphic mutations in the PAX6 gene that encodes a sequence-specific DNA-binding transcription factor for morphogenesis and evolution of the eye. We report our findings in 17 patients with PAX6 mutations associated with FVH1 or FH with aniridia and corneal opacities. Patients with three mutations, p.V78E, p.V83F and p.R128H, in the C-terminal subdomain of the paired domain (CTS) consistently have severe FH. Luciferase assays for a single reporter containing a representative PAX6 binding site indicated that the transcriptional activities of these mutations were significantly reduced, comparable to that of the truncation mutation of p.G65Rfs*5. Patients with p.P20S in the N-terminal subdomain of the paired domain, and a patient with p.N365K in the proline-serine-threonine-rich domain (PSTD) had mild FH. A patient with p.Q255L in the homeodomain had severe FH. The P20S and Q255L mutants did not affect the transcriptional activity. Mutant N365K has a retained DNA-binding activity but a reduced transcriptional activity, due to a low PSTD transactivation. These findings demonstrated that mutations associated with FVH1 underlie a functional divergence between DNA-binding ability and transcriptional activity. We conclude that a wide range of mutations in the PAX6 gene is not limited to the CST region and are responsible for FVH1.

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Section: Clinical Examinationmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 68%

Section: Clinical Examinationmentioning

confidence: 99%

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Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia

Matsushita

Izumi

Ueno

et al. 2023

Genes

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“…Isolated foveal hypoplasia without optic nerve misrouting or anterior segment dysgenesis was found in one family (family 1). Differential diagnoses includes autosomal dominant foveal hypoplasia-1 (FVH1, OMIM #136520), also referred to as foveal hypoplasia-1 with or without anterior segment anomalies and/or cataract, which is caused by heterozygous missense variants in the PAX6 gene on chromosome 11p13 [19,20]. Hemizygous mutations in GPR143 on chromosome Xp22, commonly cause ocular albinism type I (OMIM 300500); however, in a smaller number of cases, it has been reported to cause isolated congenital nystagmus-6 (OMIM 300814).…”

Section: Discussionmentioning

confidence: 99%

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia

Schiff

Tailor

Chan

et al. 2021

IJMS

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Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

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“…Foveal hypoplasia may coexist with other developmental anomalies of the organ of vision (aniridia, microphthalmia, vitiligo, achromatopsia) or it may be isolated or genetically determined. Familial foveal hypoplasia is associated with damage to the PAX6 gene [2]. Heterozygous mutations in the PAX6 gene may lead to foveal hypoplasia with a near normal ophthalmoscopic appearance of the macula, resulting in diagnostic difficulties.…”

Section: Introductionmentioning

confidence: 99%

Foveal hypoplasia in children: own observations

Niwald¹,

Piasecka²,

Cybulska-Wiktorowicz³

et al. 2022

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Autosomal dominant foveal hypoplasia without visible macular abnormalities and PAX6 mutations

Cited by 10 publications

References 22 publications

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia

Functional Characteristics of Diverse PAX6 Mutations Associated with Isolated Foveal Hypoplasia

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia

Foveal hypoplasia in children: own observations

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