Expression of three P4-phospholipid flippases—atp11a, atp11b, and atp11c in zebrafish (Danio rerio)

Hawkey-Noble, Alexia; Umali, Jurgienne; Fowler, Gerissa; French, Curtis R.

doi:10.1016/j.gep.2020.119115

Cited by 3 publications

(2 citation statements)

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“…Most importantly, Atp11a was identified as a Deiter cell defining gene that exhibits moderate expression during mouse embryonic development, followed by a marked increase in expression after birth (Shen et al 2015). Animal models for Atp11a-induced hearing loss could help elucidate the molecular mechanisms, as recent work has shown that atp11a is also expressed in the zebrafish ear (Hawkey-Noble et al 2020). Taken together this evidence suggests that the genomic complexity of ATP11A expression is similar in mouse and humans.…”

Section: Discussionmentioning

confidence: 87%

Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene

et al. 2022

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Sequencing exomes/genomes have been successful for identifying recessive genes; however, discovery of dominant genes including deafness genes (DFNA) remains challenging. We report a new DFNA gene, ATP11A, in a Newfoundland family with a variable form of bilateral sensorineural hearing loss (SNHL). Genome-wide SNP genotyping linked SNHL to DFNA33 (LOD = 4.77), a locus on 13q34 previously mapped in a German family with variable SNHL. Whole-genome sequencing identified 51 unremarkable positional variants on 13q34. Continuous clinical ascertainment identified several key recombination events and reduced the disease interval to 769 kb, excluding all but one variant. ATP11A (NC_000013.11: chr13:113534963G>A) is a novel variant predicted to be a cryptic donor splice site. RNA studies verified in silico predictions, revealing the retention of 153 bp of intron in the 3′ UTR of several ATP11A isoforms. Two unresolved families from Israel were subsequently identified with a similar, variable form of SNHL and a novel duplication (NM_032189.3:c.3322_3327+2dupGTCCAGGT) in exon 28 of ATP11A extended exon 28 by 8 bp, leading to a frameshift and premature stop codon (p.Asn1110Valfs43Ter). ATP11A is a type of P4-ATPase that transports (flip) phospholipids from the outer to inner leaflet of cell membranes to maintain asymmetry. Haploinsufficiency of ATP11A, the phospholipid flippase that specially transports phosphatidylserine (PS) and phosphatidylethanolamine (PE), could leave cells with PS/PE at the extracellular side vulnerable to phagocytic degradation. Given that surface PS can be pharmaceutically targeted, hearing loss due to ATP11A could potentially be treated. It is also likely that ATP11A is the gene underlying DFNA33.

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Section: Discussionmentioning

confidence: 87%

Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene

et al. 2022

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“…Overall, these observations support an important role for MYRF during development which have not yet been fully explored ( An et al, 2020 ). ATP11A is a ubiquitously expressed phospholipid flippase which could be important for cell-cell signaling through the cell membrane ( Takatsu et al, 2014 ; Miyano et al, 2016 ; Segawa et al, 2016 ; Hawkey-Noble et al, 2020 ). The Deciphering Mechanisms of Developmental Disorders (DMDD) project conducted a mouse knockout screen to identify genes which confer embryonic lethality and found that ATP11A knockout mice had aortic defects indicating this gene is critical for normal heart development ( Szumska et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Analysis of Turner Syndrome BAV

Gutierrez

Davis²,

Nevonen³

et al. 2022

Front. Genet.

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Turner Syndrome (TS) is a rare cytogenetic disorder caused by the complete loss or structural variation of the second sex chromosome. The most common cause of early mortality in TS results from a high incidence of left-sided congenital heart defects, including bicuspid aortic valve (BAV), which occurs in about 30% of individuals with TS. BAV is also the most common congenital heart defect in the general population with a prevalence of 0.5–2%, with males being three-times more likely to have a BAV than females. TS is associated with genome-wide hypomethylation when compared to karyotypically normal males and females. Alterations in DNA methylation in primary aortic tissue are associated with BAV in euploid individuals. Here we show significant differences in DNA methylation patterns associated with BAV in TS found in peripheral blood by comparing TS BAV (n = 12), TS TAV (n = 13), and non-syndromic BAV (n = 6). When comparing TS with BAV to TS with no heart defects we identified a differentially methylated region encompassing the BAV-associated gene MYRF, and enrichment for binding sites of two known transcription factor contributors to BAV. When comparing TS with BAV to euploid women with BAV, we found significant overlapping enrichment for ChIP-seq transcription factor targets including genes in the NOTCH1 pathway, known for involvement in the etiology of non-syndromic BAV, and other genes that are essential regulators of heart valve development. Overall, these findings suggest that altered DNA methylation affecting key aortic valve development genes contributes to the greatly increased risk for BAV in TS.

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