Structural aspects of HDAC8 mechanism and dysfunction in Cornelia de Lange syndrome spectrum disorders.

Cornelia de Lange Syndrome (CdLS) encompasses a broad spectrum of phenotypes characterized by distinctive craniofacial abnormalities, limb malformations, growth retardation, and intellectual disability. CdLS spectrum disorders are referred to as cohesinopathies, with ∼70% of patients having a mutation in a gene encoding a core cohesin protein (SMC1A, SMC3, or RAD21) or a cohesin regulatory protein (NIPBL or HDAC8). Notably, the regulatory function of HDAC8 in cohesin biology has only recently been discovered. This Zn2+ -dependent hydrolase catalyzes the deacetylation of SMC3, a necessary step for cohesin recycling during the cell cycle. To date, 23 different missense mutants in the gene encoding HDAC8 have been identified in children with developmental features that overlap those of CdLS. Enzymological, biophysical, and structural studies of CdLS HDAC8 protein mutants have yielded critical insight on compromised catalysis in vitro. Most CdLS HDAC8 mutations trigger structural changes that directly or indirectly impact substrate binding and catalysis. Additionally, several mutations significantly compromise protein thermostability. Intriguingly, catalytic activity in many HDAC8 mutants can be partially or fully restored by an N-acylthiourea activator, suggesting a plausible strategy for the chemical rescue of compromised HDAC8 catalysis in vivo.

Deardorff MA ，Porter NJ ，Christianson DW 《-》

Biochemical and structural characterization of HDAC8 mutants associated with Cornelia de Lange syndrome spectrum disorders.

Decroos C ，Christianson NH ，Gullett LE ，Bowman CM ，Christianson KE ，Deardorff MA ，Christianson DW ... -  《-》

Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders.

Decroos C ，Bowman CM ，Moser JA ，Christianson KE ，Deardorff MA ，Christianson DW ... -  《-》

HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle.

Deardorff MA ，Bando M ，Nakato R ，Watrin E ，Itoh T ，Minamino M ，Saitoh K ，Komata M ，Katou Y ，Clark D ，Cole KE ，De Baere E ，Decroos C ，Di Donato N ，Ernst S ，Francey LJ ，Gyftodimou Y ，Hirashima K ，Hullings M ，Ishikawa Y ，Jaulin C ，Kaur M ，Kiyono T ，Lombardi PM ，Magnaghi-Jaulin L ，Mortier GR ，Nozaki N ，Petersen MB ，Seimiya H ，Siu VM ，Suzuki Y ，Takagaki K ，Wilde JJ ，Willems PJ ，Prigent C ，Gillessen-Kaesbach G ，Christianson DW ，Kaiser FJ ，Jackson LG ，Hirota T ，Krantz ID ，Shirahige K ... -  《-》

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Kaiser FJ ，Ansari M ，Braunholz D ，Concepción Gil-Rodríguez M ，Decroos C ，Wilde JJ ，Fincher CT ，Kaur M ，Bando M ，Amor DJ ，Atwal PS ，Bahlo M ，Bowman CM ，Bradley JJ ，Brunner HG ，Clark D ，Del Campo M ，Di Donato N ，Diakumis P ，Dubbs H ，Dyment DA ，Eckhold J ，Ernst S ，Ferreira JC ，Francey LJ ，Gehlken U ，Guillén-Navarro E ，Gyftodimou Y ，Hall BD ，Hennekam R ，Hudgins L ，Hullings M ，Hunter JM ，Yntema H ，Innes AM ，Kline AD ，Krumina Z ，Lee H ，Leppig K ，Lynch SA ，Mallozzi MB ，Mannini L ，McKee S ，Mehta SG ，Micule I ，Care4Rare Canada Consortium ，Mohammed S ，Moran E ，Mortier GR ，Moser JA ，Noon SE ，Nozaki N ，Nunes L ，Pappas JG ，Penney LS ，Pérez-Aytés A ，Petersen MB ，Puisac B ，Revencu N ，Roeder E ，Saitta S ，Scheuerle AE ，Schindeler KL ，Siu VM ，Stark Z ，Strom SP ，Thiese H ，Vater I ，Willems P ，Williamson K ，Wilson LC ，University of Washington Center for Mendelian Genomics ，Hakonarson H ，Quintero-Rivera F ，Wierzba J ，Musio A ，Gillessen-Kaesbach G ，Ramos FJ ，Jackson LG ，Shirahige K ，Pié J ，Christianson DW ，Krantz ID ，Fitzpatrick DR ，Deardorff MA ... -  《-》