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Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder

In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two...

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Autores principales: Han, Ji Hoon, Ryan, Gavin, Guy, Alyson, Liu, Lu, Quinodoz, Mathieu, Helbling, Ingrid, Lai-Cheong, Joey E, Barwell, Julian, Folcher, Marc, McGrath, John A, Moss, Celia, Rivolta, Carlo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239743/
https://www.ncbi.nlm.nih.gov/pubmed/34999892
http://dx.doi.org/10.1093/hmg/ddab368
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author Han, Ji Hoon
Ryan, Gavin
Guy, Alyson
Liu, Lu
Quinodoz, Mathieu
Helbling, Ingrid
Lai-Cheong, Joey E
Barwell, Julian
Folcher, Marc
McGrath, John A
Moss, Celia
Rivolta, Carlo
author_facet Han, Ji Hoon
Ryan, Gavin
Guy, Alyson
Liu, Lu
Quinodoz, Mathieu
Helbling, Ingrid
Lai-Cheong, Joey E
Barwell, Julian
Folcher, Marc
McGrath, John A
Moss, Celia
Rivolta, Carlo
author_sort Han, Ji Hoon
collection PubMed
description In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was haploidentical and common to all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1’s exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognized ribosomopathy.
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spelling pubmed-92397432022-06-29 Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder Han, Ji Hoon Ryan, Gavin Guy, Alyson Liu, Lu Quinodoz, Mathieu Helbling, Ingrid Lai-Cheong, Joey E Barwell, Julian Folcher, Marc McGrath, John A Moss, Celia Rivolta, Carlo Hum Mol Genet Original Article In the framework of the UK 100 000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was haploidentical and common to all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1’s exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognized ribosomopathy. Oxford University Press 2022-01-06 /pmc/articles/PMC9239743/ /pubmed/34999892 http://dx.doi.org/10.1093/hmg/ddab368 Text en © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Article
Han, Ji Hoon
Ryan, Gavin
Guy, Alyson
Liu, Lu
Quinodoz, Mathieu
Helbling, Ingrid
Lai-Cheong, Joey E
Barwell, Julian
Folcher, Marc
McGrath, John A
Moss, Celia
Rivolta, Carlo
Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title_full Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title_fullStr Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title_full_unstemmed Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title_short Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder
title_sort mutations in the ribosome biogenesis factor gene ltv1 are linked to liphak syndrome, a novel poikiloderma-like disorder
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9239743/
https://www.ncbi.nlm.nih.gov/pubmed/34999892
http://dx.doi.org/10.1093/hmg/ddab368
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