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Characterizing the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirschhorn syndrome

journal contribution
posted on 2023-06-08, 11:15 authored by Claudia Kerzendorfer, Femke Hannes, Rita Colnaghi, Iga Abramowicz, Gillian Carpenter, Joris Robert Vermeesch, Mark O'DriscollMark O'Driscoll
Wolf-Hirschhorn syndrome (WHS) is a contiguous gene deletion disorder associated with the distal part of the short arm of chromosome 4 (4p16.3). Employing a unique panel of patient-derived cell lines with differing-sized 4p deletions, we provide evidence that haploinsufficiency of SLBP and/or WHSC2 (NELF-A) contributes to several novel cellular phenotypes of WHS, including delayed progression from S-phase into M-phase, reduced DNA replication in asynchronous culture and altered higher order chromatin assembly. The latter is evidenced by reduced histone-chromatin association, elevated levels of soluble chaperone-bound histone H3 and increased sensitivity to micrococcal nuclease digestion in WHS patient-derived cells. We also observed increased camptothecin-induced inhibition of DNA replication and hypersensitivity to killing. Our work provides a novel pathogenomic insight into the aetiology of WHS by describing it, for the first time, as a disorder of impaired chromatin reorganization. Delayed cell-cycle progression and impaired DNA replication likely underlie or contribute to microcephaly, pre- and postnatal growth retardation, which constitute the core clinical features of WHS.

History

Publication status

  • Published

Journal

Human Molecular Genetics

ISSN

0964-6906

Publisher

Oxford University Press

Issue

10

Volume

21

Page range

2181-2193

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-04-19

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