The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.
POLA1
Dyskeratosis Congenita
Telomeres
ncRNAs
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: Germany
ID NLM: 101487380
Informations de publication
Date de publication:
28 Aug 2024
28 Aug 2024
Historique:
received:
10
04
2024
accepted:
18
07
2024
revised:
12
07
2024
medline:
31
8
2024
pubmed:
31
8
2024
entrez:
28
8
2024
Statut:
aheadofprint
Résumé
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome, caused by genetic mutations that principally affect telomere biology. Approximately 35% of cases remain uncharacterised at the genetic level. To explore the genetic landscape, we conducted genetic studies on a large collection of clinically diagnosed cases of DC as well as cases exhibiting features resembling DC, referred to as 'DC-like' (DCL). This led us to identify several novel pathogenic variants within known genetic loci and in the novel X-linked gene, POLA1. In addition, we have also identified several novel variants in POT1 and ZCCHC8 in multiple cases from different families expanding the allelic series of DC and DCL phenotypes. Functional characterisation of novel POLA1 and POT1 variants, revealed pathogenic effects on protein-protein interactions with primase, CTC1-STN1-TEN1 (CST) and shelterin subunit complexes, that are critical for telomere maintenance. ZCCHC8 variants demonstrated ZCCHC8 deficiency and signs of pervasive transcription, triggering inflammation in patients' blood. In conclusion, our studies expand the current genetic architecture and broaden our understanding of disease mechanisms underlying DC and DCL disorders.
Identifiants
pubmed: 39198715
doi: 10.1038/s44321-024-00118-x
pii: 10.1038/s44321-024-00118-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : UKRI | Medical Research Council (MRC)
ID : MR/P018440/1
Organisme : UKRI | Medical Research Council (MRC)
ID : MR/P018440/1
Organisme : UKRI | Medical Research Council (MRC)
ID : MR/P018440/1
Organisme : Blood Cancer UK
ID : 14032
Pays : United Kingdom
Organisme : Blood Cancer UK
ID : 14032
Pays : United Kingdom
Informations de copyright
© 2024. The Author(s).
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