Knockout of DNase1l1l abrogates lens denucleation process and causes cataract in zebrafish

Zhang, Jing; Cui, Wenwen; Du, Chunxiao; Huang, Yu-Wen; Pi, Xiahui; Guo, Wei; Wang, Jungai; Huang, Weikang; Chen, Danling; Li, Jing; Li, Hui; Zhang, Jun; Ma, Yi; Mu, Hongmei; Zhang, Shuman; Liu, Mugen; Cui, Xiukun; Hu, Yanzhong

doi:10.1016/j.bbadis.2020.165724

Cited by 16 publications

(13 citation statements)

References 58 publications

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“…In the present study, N-cadherin and cell nuclei staining at 3 dpf highlighted lens fibre cell defects in epha2b morphant zebrafish similar to that observed in other zebrafish cataract models, suggesting a conserved role in lens fibre cell development [50,51]. Mutations in epha2 may disrupt the adherens junctions in the developing lens, which interfere with the molecular signalling of the optic cup, resulting in microphthalmia.…”

Section: Discussionsupporting

confidence: 82%

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

Harding

Toms

Schiff

et al. 2021

IJMS

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EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic EPHA2 variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, ≥2 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with >90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic EPHA2 variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C>T, p.(Pro584Leu) and (ii) splice site c.2826-9G>A. To functionally validate pathogenicity, morpholino knockdown of epha2a/epha2b in zebrafish resulted in significantly reduced eye size ± cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the epha2b knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of EPHA2 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.

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Section: Discussionsupporting

confidence: 82%

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

Harding

Toms

Schiff

et al. 2021

IJMS

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“…Very little is known about the role of DNase1L1L which does not show any known functional motif at the C-terminal end. DNase1L1L was reported to be uniquely expressed in zebrafish lens and responsible for nuclear DNA degradation during lens development 55 .…”

Section: Discussionmentioning

confidence: 99%

Origin and significance of the human DNase repertoire

Mori

Delfino

Pibiri

et al. 2022

Sci Rep

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The human genome contains four DNase1 and two DNase2 genes. The origin and functional specialization of this repertoire are not fully understood. Here we use genomics and transcriptomics data to infer the evolutionary history of DNases and investigate their biological significance. Both DNase1 and DNase2 families have expanded in vertebrates since ~ 650 million years ago before the divergence of jawless and jawed vertebrates. DNase1, DNase1L1, and DNase1L3 co-existed in jawless fish, whereas DNase1L2 originated in amniotes by tandem duplication of DNase1. Among the non-human DNases, DNase1L4 and newly identified DNase1L5 derived from early duplications that were lost in terrestrial vertebrates. The ancestral gene of the DNase2 family, DNase2b, has been conserved in synteny with the Uox gene across 700 million years of animal evolution,while DNase2 originated in jawless fish. DNase1L1 acquired a GPI-anchor for plasma membrane attachment in bony fishes, and DNase1L3 acquired a C-terminal basic peptide for the degradation of microparticle DNA in jawed vertebrates. The appearance of DNase1L2, with a distinct low pH optimum and skin localization, is among the amniote adaptations to life on land. The expansion of the DNase repertoire in vertebrates meets the diversified demand for DNA debris removal in complex multicellular organisms.

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“…Very little is known about the role of DNase1L1L which does not show any known functional motif at the C-terminal end. DNase1L1L was reported to be uniquely expressed in zebra sh lens and responsible for nuclear DNA degradation during lens development 52 .…”

Section: Discussionmentioning

confidence: 99%

Origin and significance of the human DNase repertoire

Mori

Delfino

Pibiri

et al. 2022

Preprint

View full text Add to dashboard Cite

The human genome contains four DNase1 and two DNase2 genes. The origin and functional specialization of this repertoire are not fully understood. Here we use genomics and transcriptomics data to infer the evolutionary history of DNases and investigate their biological significance. Both DNase1 and DNase2 families have expanded in vertebrates since ~650 million years ago before the divergence of jawless and jawed vertebrates. DNase1, DNase1L1, and DNase1L3 co-existed in jawless fish, whereas DNase1L2 originated in amniotes by tandem duplication of DNase1. Among the non-human DNases, DNase1L4 and newly identified DNase1L5 derived from early duplications that were lost in terrestrial vertebrates. The ancestral gene of the DNase2 family, DNase2b, has been conserved in synteny with the Uox gene across 700 million years of animal evolution,while DNase2 originated in jawless fish. DNase1L1 acquired a GPI-anchor for plasma membrane attachment in bony fishes, and DNase1L3 acquired a C-terminal basic peptide for the degradation of microparticle DNA in jawed vertebrates. The appearance of DNase1L2, with a distinct low pH optimum and skin localization, is among the amniote adaptations to life on land. The expansion of the DNase repertoire in vertebrates meets the diversified demand for DNA debris removal in complex multicellular organisms.

show abstract

Knockout of DNase1l1l abrogates lens denucleation process and causes cataract in zebrafish

Cited by 16 publications

References 58 publications

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

Origin and significance of the human DNase repertoire

Origin and significance of the human DNase repertoire

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