New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

Ceroni, Fabiola; Aguilera-Garcia, Domingo; Chassaing, Nicolas; Bax, Dorine A.; Blanco‐Kelly, Fiona; Ramos, Patricia; Tarilonte, M.; Villaverde, Cristina; Silva, Luciana Rodrigues Jacy da; Ballesta-Martínez, Maria Juliana; Sánchez-Soler, María José; Holt, R. J.; Cooper-Charles, Lisa; Bruty, Jonathan; Wallis, Yvonne; McMullan, Dominic; Hoffman, Jonathan; Bunyan, David J.; Stewart, Alison; Stewart, Helen; Lachlan, Katherine; Fryer, Alan; McKay, Victoria; Roume, J.; Dureau, P.; Saggar, Anand; Griffiths, Michael; Calvas, Patrick; Ayuso, Carmen; Cortón, Marta; Ragge, Nicola

doi:10.1007/s00439-018-1875-2

Cited by 44 publications

(33 citation statements)

References 69 publications

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“…To investigate further the role of GJA8 in A/M, Ceroni et al (Ceroni et al 2018) analyzed a large cohort of individuals presenting with a wide range of developmental eye anomalies, mainly A/M and coloboma. This study identified 6 likely pathogenic sequence variants in 7 independent families, including the variant previously reported by Ma et al (Ma et al 2016).…”

Section: Gja8 (Gap Junction Protein Alpha 8)mentioning

confidence: 99%

“…Interestingly, in all 6 families where segregation analysis could be performed, these variants co-segregated with both early onset cataracts and microphthalmia, supporting the hypothesis that the gene may be involved a broader range of human developmental eye anomalies. The missense variant p.(Gly94Arg) (c.280G>A, NM_005267.4) for which segregation analysis could not be performed was identified in a child with congenital aphakia, sclerocornea, microphthalmia and coloboma (Ceroni et al 2018) (Fig. 3b,c).…”

Section: Gja8 (Gap Junction Protein Alpha 8)mentioning

confidence: 99%

“…Right and left eyes, respectively, of a male diagnosed with bilateral microphthalmia, iris and optic disc coloboma, corneal opacity, bilateral congenital aphakia and primary glaucoma. The patient carries a missense variant in GJA8 (Ceroni et al 2018) 3.a.…”

Section: B-cmentioning

confidence: 99%

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Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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Eye formation is the result of coordinated induction and differentiation processes during embryogenesis. Disruption of any one of these events has the potential to cause ocular growth and structural defects, such as anophthalmia and microphthalmia (A/M). A/M can be isolated or occur with systemic anomalies, when they may form part of a recognizable syndrome. Their etiology includes genetic and environmental factors; several hundred genes involved in ocular development have been identified in humans or animal models. In humans, around 30 genes have been repeatedly implicated in A/M families, although many other genes have been described in single cases or families, and some genetic syndromes include eye anomalies occasionally as part of a wider phenotype. As a result of this broad genetic heterogeneity, with one or two notable exceptions, each gene explains only a small percentage of cases. Given the overlapping phenotypes, these genes can be most efficiently tested on panels or by whole exome/genome sequencing for the purposes of molecular diagnosis. However, despite whole exome/genome testing more than half of patients currently remain without a molecular diagnosis. The proportion of undiagnosed cases is even higher in those individuals with unilateral or milder phenotypes. Furthermore, even when a strong gene candidate is available for a patient, issues of incomplete penetrance and germinal mosaicism make diagnosis and genetic counselling challenging. In this review, we present the main genes implicated in nonsyndromic human A/M phenotypes and, for practical purposes, classify them according to the most frequent or predominant phenotype each is associated with. Our intention is that this will allow clinicians to rank and prioritize their molecular analyses and interpretations according to the phenotypes of their patients.

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Section: Gja8 (Gap Junction Protein Alpha 8)mentioning

confidence: 99%

Section: Gja8 (Gap Junction Protein Alpha 8)mentioning

confidence: 99%

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Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

et al. 2019

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“…To date, 90 heterozygous variants have been described in families with autosomal-dominant cataract, and a single homozygous variant in autosomalrecessive cataract has been found in GJA8, associated not only with inherited cataract but also age-related cataract and other eye anomalies including microcornea, microphthalmia and corneal opacification. 37…”

Section: Membrane Proteins Connexinsmentioning

confidence: 99%

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

et al. 2020

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Cataract is the most common cause of blindness in the world; during infancy and early childhood, it frequently results in visual impairment. Congenital cataracts are phenotypically and genotypically heterogeneous and can occur in isolation or in association with other systemic disorders. Significant progress has been made in identifying the molecular genetic basis of cataract; 115 genes to date have been found to be associated with syndromic and non-syndromic cataract and 38 disease-causing genes have been identified to date to be associated with isolated cataract. In this review, we briefly discuss lens development and cataractogenesis, detail the variable cataract phenotypes and molecular mechanisms, including genotype-phenotype correlations, and explore future novel therapeutic avenues including cellular therapies and pharmacological treatments.

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“…In humans, a subpopulation of colobomata is a result of mutations in developmentally important genes, however, the origins for many OF closure defects are unknown (for reviews, see (3,7,8,13,14)). Additional genes have been identified in animal models; substantial progress has been made in understanding critical processes, including growth and patterning of the ventral optic cup and optic nerve head (15- 19), cell-cell contact and signaling (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), crosstalk with migrating hyaloid precursors and extracellular matrix components (31)(32)(33)(34)(35)(36), cytoskeleton dynamics (37,38), epigenetics (39), degradation of ECM and cellular proteins (40)(41)(42), programmed cell death, survival and cell proliferation (43,44) (for reviews, see (7,8,13)). Elegant in vivo imaging studies in zebrafish and excellent anatomical analyses in chick have characterized important morphogenetic and cellular behavior (20,27,34,(45)(46)(47)(48)(49).…”

Section: Introductionmentioning

confidence: 99%

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

Sun

Ramirez

Spiller

et al. 2020

Preprint

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Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (1~ in 5,000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggest multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicates that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased RPE proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F--actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during optic fissure closure.

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New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies

Cited by 44 publications

References 69 publications

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

Inherited cataracts: molecular genetics, clinical features, disease mechanisms and novel therapeutic approaches

Nf2 fine-tunes proliferation and tissue alignment during closure of the optic fissure in the embryonic mouse eye

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