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

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). G...

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Autores principales: Pater, Justin A., Penney, Cindy, O’Rielly, Darren D., Griffin, Anne, Kamal, Lara, Brownstein, Zippora, Vona, Barbara, Vinkler, Chana, Shohat, Mordechai, Barel, Ortal, French, Curtis R., Singh, Sushma, Werdyani, Salem, Burt, Taylor, Abdelfatah, Nelly, Houston, Jim, Doucette, Lance P., Squires, Jessica, Glaser, Fabian, Roslin, Nicole M., Vincent, Daniel, Marquis, Pascale, Woodland, Geoffrey, Benoukraf, Touati, Hawkey-Noble, Alexia, Avraham, Karen B., Stanton, Susan G., Young, Terry-Lynn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035003/
https://www.ncbi.nlm.nih.gov/pubmed/35278131
http://dx.doi.org/10.1007/s00439-022-02444-x
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author Pater, Justin A.
Penney, Cindy
O’Rielly, Darren D.
Griffin, Anne
Kamal, Lara
Brownstein, Zippora
Vona, Barbara
Vinkler, Chana
Shohat, Mordechai
Barel, Ortal
French, Curtis R.
Singh, Sushma
Werdyani, Salem
Burt, Taylor
Abdelfatah, Nelly
Houston, Jim
Doucette, Lance P.
Squires, Jessica
Glaser, Fabian
Roslin, Nicole M.
Vincent, Daniel
Marquis, Pascale
Woodland, Geoffrey
Benoukraf, Touati
Hawkey-Noble, Alexia
Avraham, Karen B.
Stanton, Susan G.
Young, Terry-Lynn
author_facet Pater, Justin A.
Penney, Cindy
O’Rielly, Darren D.
Griffin, Anne
Kamal, Lara
Brownstein, Zippora
Vona, Barbara
Vinkler, Chana
Shohat, Mordechai
Barel, Ortal
French, Curtis R.
Singh, Sushma
Werdyani, Salem
Burt, Taylor
Abdelfatah, Nelly
Houston, Jim
Doucette, Lance P.
Squires, Jessica
Glaser, Fabian
Roslin, Nicole M.
Vincent, Daniel
Marquis, Pascale
Woodland, Geoffrey
Benoukraf, Touati
Hawkey-Noble, Alexia
Avraham, Karen B.
Stanton, Susan G.
Young, Terry-Lynn
author_sort Pater, Justin A.
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-022-02444-x.
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spelling pubmed-90350032022-05-06 Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene Pater, Justin A. Penney, Cindy O’Rielly, Darren D. Griffin, Anne Kamal, Lara Brownstein, Zippora Vona, Barbara Vinkler, Chana Shohat, Mordechai Barel, Ortal French, Curtis R. Singh, Sushma Werdyani, Salem Burt, Taylor Abdelfatah, Nelly Houston, Jim Doucette, Lance P. Squires, Jessica Glaser, Fabian Roslin, Nicole M. Vincent, Daniel Marquis, Pascale Woodland, Geoffrey Benoukraf, Touati Hawkey-Noble, Alexia Avraham, Karen B. Stanton, Susan G. Young, Terry-Lynn Hum Genet Original Investigation 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-022-02444-x. Springer Berlin Heidelberg 2022-03-12 2022 /pmc/articles/PMC9035003/ /pubmed/35278131 http://dx.doi.org/10.1007/s00439-022-02444-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Investigation
Pater, Justin A.
Penney, Cindy
O’Rielly, Darren D.
Griffin, Anne
Kamal, Lara
Brownstein, Zippora
Vona, Barbara
Vinkler, Chana
Shohat, Mordechai
Barel, Ortal
French, Curtis R.
Singh, Sushma
Werdyani, Salem
Burt, Taylor
Abdelfatah, Nelly
Houston, Jim
Doucette, Lance P.
Squires, Jessica
Glaser, Fabian
Roslin, Nicole M.
Vincent, Daniel
Marquis, Pascale
Woodland, Geoffrey
Benoukraf, Touati
Hawkey-Noble, Alexia
Avraham, Karen B.
Stanton, Susan G.
Young, Terry-Lynn
Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title_full Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title_fullStr Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title_full_unstemmed Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title_short Autosomal dominant non-syndromic hearing loss maps to DFNA33 (13q34) and co-segregates with splice and frameshift variants in ATP11A, a phospholipid flippase gene
title_sort autosomal dominant non-syndromic hearing loss maps to dfna33 (13q34) and co-segregates with splice and frameshift variants in atp11a, a phospholipid flippase gene
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035003/
https://www.ncbi.nlm.nih.gov/pubmed/35278131
http://dx.doi.org/10.1007/s00439-022-02444-x
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