Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

Daruich, Alejandra; Duncan, Melinda K.; Robert, Matthieu P.; Lagali, Neil; Semina, Elena V.; Aberdam, Daniel; Ferrari, Stefano; Romano, Vito; Benkortebi, Rabia; Vergnes, Nathalie de; Polak, Michel; Chiambaretta, Frédéric; Nischal, Ken K.; Valleix, Sophie; Bremond-Gignac, Dominique

doi:10.1016/j.preteyeres.2022.101133

Cited by 33 publications

(24 citation statements)

References 356 publications

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“…Однако они имеют генетически обусловленные различия. Аниридии встречаются с распространенностью 1 : 50 000-100 000 живорожденных и связаны с мутациями в гене PAX6, который управляет эмбриональным развитием нескольких тканей и органов, включая глаза, поджелудочную железу и ЦНС [9,10]. При врожденных аниридиях главной, но не единственной причиной слабовидения и нистагма является отсутствие радужной оболочки, хотя часто также встречается гипоплазия фовеа (центральной ямки сетчатки).…”

Section: обоснованиеunclassified

“…Имеются данные о когнитивных нарушениях, нарушениях центральной обработки слухового восприятия и сна при врожденной аниридии [10,11]. Синдромальные формы врожденных аниридий являются крайне редкими заболеваниями, среди них чаще выявляется синдром WAGR (опухоль Вильмса, аниридия, аномалии мочеполовой системы и умственная отсталость), представляющий собой редкий синдром делеции смежных генов, характеризующийся делецией de novo хромосомы 11p13, включая ген WT1 (опухоль Вильмса и аномалии мочеполовой системы) и ген PAX6 (аниридия) [10]. К развитию умственной отсталости и ожирения при синдроме WAGR считают причастным ген BDNF [10,12], но также рассматриваются и гены SLC1A2 и PRRG4 [13].…”

Section: обоснованиеunclassified

“…Синдромальные формы врожденных аниридий являются крайне редкими заболеваниями, среди них чаще выявляется синдром WAGR (опухоль Вильмса, аниридия, аномалии мочеполовой системы и умственная отсталость), представляющий собой редкий синдром делеции смежных генов, характеризующийся делецией de novo хромосомы 11p13, включая ген WT1 (опухоль Вильмса и аномалии мочеполовой системы) и ген PAX6 (аниридия) [10]. К развитию умственной отсталости и ожирения при синдроме WAGR считают причастным ген BDNF [10,12], но также рассматриваются и гены SLC1A2 и PRRG4 [13]. Глазокожная форма альбинизма также относится к редким генетическим состояниям; известно, что распространенность всех форм альбинизма в западных странах составляет от 1 : 14 000 до 1 : 17 000 [14], соответственно, глазокожная форма встречается реже.…”

Section: обоснованиеunclassified

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Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

et al. 2023

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Background. The role of recently discovered neurospecific peptides in the pathogenesis of acute and progressive neurologic disorders, their neuroprotective features, and possibilities to use them as markers for the course and prognosis of certain diseases have been actively studied in recent decades. However, neurospecific peptides are almost not studied in chronic residual diseases. In our study we measured the levels of neurospecific peptides and some other markers to achieve understanding of general neurophysiological trends in congenital and acquired chronic non-progressive brain pathology with reference to the selection of relevant groups — study objects. Objective. The aim of the study is to study patterns of neurospecific peptides, neurotransmitters and neuroreceptor markers distribution in the serum of children with various pathogenetic variants of chronic neuropathology. Methods. The study included children from 3 to 16 years old with different pathologies. The sample was divided into groups by pathology type: no sensory and neurological disorders, congenital sensory deficit due to mutation of genes expressed and not expressed in the brain, early acquired sensory deficit of multifactorial nature, congenital mild and severe organic disorders of central nervous system (CNS) in residual stage without baseline sensory deficit, acquired functional CNS disorders without baseline organic defect and sensory deficit. The following laboratory data (neurophysiological components) was studied: nerve growth factor, brain-derived neurotropic factor, neurotrophin-3, neurotrophin-4, neuregulin-1-beta-1, beta-secretase, sirtuin-1, synaptophysin, neuronal nitric oxide synthase, and anti-NR2 glutamate receptor antibodies. The parameters of cognitive activity, sense of vision, sense of smell, and acoustic sense were also evaluated. Results. The study included 274 participants. Neuropeptides and markers have shown a variable degree and range in the group spectrum of differences from normal levels. The most variable in the examined sample was NO-synthase, as well as levels of both neurotrophins, beta-secretase, and glutamate receptor marker. All visual deficits were associated with increased NO-synthase levels (p < 0.001). Neuroplasticity peptides (beta-secretase, neurotrophin-3 and 4) have been activated in all pathological conditions. Nerve growth factor and brain-derived neurotropic factor were specifically activated in mild organic CNS lesions (mild cognitive impairments), while neuregulin — in congenital genetically determined visual deficits. There was no specific activation of neuropeptides and NO-synthase level tended to decrease in cases of severe CNS lesions. Conclusion. The study results suggest that all types of early visual impairment are associated with increased physiological neuronal activity, and non-organic neurological functional disorders — mainly with increased physiological synaptic activity. General neuroplasticity processes were activated in all cases of visual deficits but more specific. However, more specific and well-studied processes were activated in mild organic CNS lesions, and neuroplasticity processes did not activate adequately in severe organic CNS lesions probably due to the limited neuronal and synaptic resources.

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Section: обоснованиеunclassified

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Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

et al. 2023

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“…Aniridia is an autosomal dominant disorder caused by haploinsufficiency of the highly conserved transcriptional factor PAX6 (Paired-box gene 6), which is involved in the morphogenesis and maintenance of ocular structures [ 2 ]. Patients with PAX6 -related abnormalities show overlapping presentations of different anterior and posterior segment anomalies [ 1 , 3 , 4 ]. Patients carrying PAX6 pathogenic variants usually present with iris defects to varying degrees ranging from complete absence to a normal iris with minor abnormalities [ 1 , 3 , 4 ], but foveal hypoplasia, responsible for congenital low vision, is even more frequent [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Patients with PAX6 -related abnormalities show overlapping presentations of different anterior and posterior segment anomalies [ 1 , 3 , 4 ]. Patients carrying PAX6 pathogenic variants usually present with iris defects to varying degrees ranging from complete absence to a normal iris with minor abnormalities [ 1 , 3 , 4 ], but foveal hypoplasia, responsible for congenital low vision, is even more frequent [ 3 ]. Iris and foveal hypoplasia are often accompanied by other ocular manifestations, such as early-onset glaucoma, cataract, and limbal dysfunction, among others, leading to a loss of visual acuity throughout life [ 1 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Minigene Splicing Assays and Long-Read Sequencing to Unravel Pathogenic Deep-Intronic Variants in PAX6 in Congenital Aniridia

Tamayo

Núñez‐Moreno

Ruiz

et al. 2023

IJMS

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PAX6 haploinsufficiency causes aniridia, a congenital eye disorder that involves the iris, and foveal hypoplasia. Comprehensive screening of the PAX6 locus, including the non-coding regions, by next-generation sequencing revealed four deep-intronic variants with potential effects on pre-RNA splicing. Nevertheless, without a functional analysis, their pathogenicity could not be established. We aimed to decipher their impact on the canonical PAX6 splicing using in vitro minigene splicing assays and nanopore-based long-read sequencing. Two multi-exonic PAX6 constructs were generated, and minigene assays were carried out. An aberrant splicing pattern was observed for two variants in intron 6, c.357+136G>A and c.357+334G>A. In both cases, several exonization events, such as pseudoexon inclusions and partial intronic retention, were observed due to the creation or activation of new/cryptic non-canonical splicing sites, including a shared intronic donor site. In contrast, two variants identified in intron 11, c.1032+170A>T and c.1033-275A>C, seemed not to affect splicing processes. We confirmed the high complexity of alternative splicing of PAX6 exon 6, which also involves unreported cryptic intronic sites. Our study highlights the importance of integrating functional studies into diagnostic algorithms to decipher the potential implication of non-coding variants, usually classified as variants of unknown significance, thus allowing variant reclassification to achieve a conclusive genetic diagnosis.

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Toward Corneal Limbus In Vitro Model: Regulation of hPSC‐LSC Phenotype by Matrix Stiffness and Topography During Cell Differentiation Process

Kauppila

Mörö

Valle‐Delgado

et al. 2023

Adv Healthcare Materials

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A functional limbal epithelial stem cells (LSC) niche is a vital element in the regular renewal of the corneal epithelium by LSCs and maintenance of good vision. However, little is known about its unique structure and mechanical properties on LSC regulation, creating a significant gap in development of LSC‐based therapies. Herein, the effect of mechanical and architectural elements of the niche on human pluripotent derived LSCs (hPSC‐LSC) phenotype and growth is investigated in vitro. Specifically, three formulations of polyacrylamide gels with different controlled stiffnesses are used for culture and characterization of hPSC‐LSCs from different stages of differentiation. In addition, limbal mimicking topography in polydimethylsiloxane is utilized for culturing hPSC‐LSCs at early time point of differentiation. For comparison, the expression of selected key proteins of the corneal cells is analyzed in their native environment through whole mount staining of human donor corneas. The results suggest that mechanical response and substrate preference of the cells is highly dependent on their developmental stage. In addition, data indicate that cells may carry possible mechanical memory from previous culture matrix, both highlighting the importance of mechanical design of a functional in vitro limbus model.

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Congenital aniridia beyond black eyes: From phenotype and novel genetic mechanisms to innovative therapeutic approaches

Cited by 33 publications

References 356 publications

Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

Levels of Neurospecific Peptides, Neurotransmitters and Neuroreceptor Markers in the Serum of Children with Various Sensory Disorders, Mild Cognitive Impairments and Other Neuropathology

Minigene Splicing Assays and Long-Read Sequencing to Unravel Pathogenic Deep-Intronic Variants in PAX6 in Congenital Aniridia

Toward Corneal Limbus In Vitro Model: Regulation of hPSC‐LSC Phenotype by Matrix Stiffness and Topography During Cell Differentiation Process

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