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

[wolf-hirschhorn syndrome]

Wolf-Hirschhorn syndrome (WHS ) is a contiguous gene deletion disorder associated with the distal part of the short arm of chromosome 4 (4 p 16 .3 ). Employing a unique panel of patient-derived cell lines with differing-sized 4 p deletions , we provide evidence that haploinsufficiency of SLBP and /or WHSC 2 (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 H 3 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 .