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

Kerzendorfer, Claudia, Hannes, Femke, Colnaghi, Rita, Abramowicz, Iga, Carpenter, Gillian, Vermeesch, Joris Robert and O'Driscoll, Mark (2012) Characterizing the functional consequences of haploinsufficiency of NELF-A (WHSC2) and SLBP identifies novel cellular phenotypes in Wolf-Hirschhorn syndrome. Human Molecular Genetics, 21 (10). pp. 2181-2193. ISSN 0964-6906

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: R Medicine > RB Pathology > RB127 Manifestations of disease
R Medicine > RB Pathology > RB151 Theories of disease. Etiology. Pathogenesis
Depositing User: Mark O'Driscoll
Date Deposited: 19 Apr 2012 08:37
Last Modified: 07 Mar 2017 08:02
URI: http://sro.sussex.ac.uk/id/eprint/38513

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