POT1 recruits and regulates CST-Polα/primase at human telomeres

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.

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Polygenic modifiers of expressivity in telomere biology disorders

Poeschla,

Arora,

Walne

et al. 2024

Preprint

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Variable expressivity, where individuals carrying identical genetic variants display diverse phenotypes, presents an important challenge in clinical genetics. This is exemplified by the telomere biology disorders (TBDs), which exhibit tremendous clinical heterogeneity despite their presumed monogenic nature, even among individuals harboring the same pathogenic variant. Here, we studied cohorts of patients with TBDs and population biobanks to demonstrate that common genome-wide polymorphisms associated with variation in telomere length in the general population combine with large-effect causal variants to significantly impact TBD expressivity. We go on to show that polygenic variation can contribute to expressivity within a single family with a shared large-effect causal variant, and that common and rare variation converge on a shared set of genes implicated in telomere maintenance. By elucidating the role of common genetic variation in rare disease expressivity in TBDs, these results provide a framework for understanding phenotypic variability in other presumed monogenic disorders.

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POT1 recruits and regulates CST-Polα/primase at human telomeres

Cited by 3 publications

References 73 publications

At the end, it is POT1 again: Phosphorylation allows human telomeric protein POT1 to recruit the C-rich strand end replication machinery

At the end, it is POT1 again: Phosphorylation allows human telomeric protein POT1 to recruit the C-rich strand end replication machinery

The evolving genetic landscape of telomere biology disorder dyskeratosis congenita

Polygenic modifiers of expressivity in telomere biology disorders

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