Researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control gene expression and cell division, the research sheds light on this disease. CdLS causes intellectual disability, limb deformations, and other disabilities resulting from impairments in early development. First described in 1933, CdLS affects an estimated 1 in 10,000 children.

"As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders," said study leader Matthew A. Deardorff, MD, PhD, a researcher at The Children’s Hospital of Philadelphia.

The CdLS research team at CHOP has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. Mutations that perturb normal cohesin function can interfere with normal human development, Deardorff noted. Such is the case in CdLS, which exemplifies a newly recognized class of diseases called cohesinopathies.

In the current study, the scientists investigated both acetylation - how an acetyl molecule is attached to part of the cohesion complex - and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.

Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of "recharged" cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.

The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.

Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk — the likelihood of having a subsequent child with CdLS. And by providing details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease.

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