HDAC8 – Cornelia de Lange Syndrome 5

Cornelia de Lange syndrome 5 (CdLS5) is an X-linked disorder characterized by facial dysmorphisms, growth retardation, intellectual disability, and limb anomalies. HDAC8 encodes the SMC3 deacetylase critical for cohesin recycling during the cell cycle. Hemizygous and heterozygous mutations in HDAC8 disrupt cohesin dynamics and underlie CdLS5.

Genetic analyses have identified six unrelated probands with loss-of-function HDAC8 variants and 38 additional individuals harboring de novo missense and splicing defects, supporting an X-linked inheritance pattern (PMID:22885700; PMID:24403048). Most variants arise de novo, with affected females exhibiting skewed X-inactivation and mosaicism in some cases, while hemizygous males display more severe phenotypes.

The variant spectrum encompasses missense (n=23), frameshift, nonsense, splice-site, and intragenic deletions, without clear founder mutations. A prototypical variant, c.356C>G (p.Thr119Arg), abrogates deacetylase activity and recapitulates disease mechanisms in vitro (PMID:34342180).

Segregation is primarily observed as de novo events, with no evidence of multi-generational transmission due to reduced reproductive fitness in affected individuals and marked X-inactivation skewing in carrier females.

Functional studies demonstrate that HDAC8 mutations result in elevated acetylation of SMC3, impaired release of “used” cohesin from chromatin, and consistent transcriptional dysregulation across CdLS cell lines (PMID:22885700). In vitro assays confirm loss of deacetylase activity, and cellular models exhibit defective cohesin recycling.

Structural and biochemical characterizations of HDAC8 mutants (e.g., C153F, H334R) reveal local conformational perturbations that compromise catalysis and thermostability. Remarkably, small-molecule activators can partially or fully restore enzymatic function in vitro, highlighting a potential therapeutic avenue (PMID:25075551).

Integration of genetic and functional data establishes a definitive association between HDAC8 and CdLS5. Clinical sequencing of HDAC8, including copy-number analysis, is recommended for individuals with CdLS-like features. The mechanistic insights into cohesin deacetylation inform both diagnostics and the development of targeted therapies.

Key Take-home: HDAC8 mutations cause CdLS5 via loss-of-function, defining both a diagnostic marker and a potential target for activator-based treatments.

References

• Nature • 2012 • HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. PMID:22885700
• Human Molecular Genetics • 2014 • Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance. PMID:24403048
• ACS Chemical Biology • 2014 • Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders. PMID:25075551
• Molecular Genetics & Genomic Medicine • 2021 • A novel de novo HDAC8 missense mutation causing Cornelia de Lange syndrome. PMID:34342180

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