Novel Cornelia de Lange syndrome gene discovered

Aug 13 2012

By Helen Albert, Senior MedWire Reporter

Scientists have discovered that mutations in the histone deacetylase 8 gene (HDAC8) can cause the rare genetic disorder known as Cornelia de Lange syndrome (CdLS), which is characterized by intellectual disability, limb deformity, and other disabilities resulting from problems in early development.

Further investigation revealed that mutations in HDAC8 adversely affect the cohesin complex, a group of proteins involved in regulation of chromatid placement during cell division and correct transcription of genetic information from DNA to RNA.

The findings of this study, published in Nature, add to those of previous studies that have isolated mutations in the genes nipped-B-like protein (NIPBL), structural maintenance of chromosomes protein 1A (SMC1A), and SMC3 as being causative for the condition.

"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 Deardorff (University of Pennsylvania Perelman School of Medicine, Philadelphia, USA) in a press statement.

The researchers identified loss-of-function mutations in HDAC8 in six CdLS children. These mutations resulted in increased acetylation of SMC3 protein and inefficient dissolution of the cohesin complex during the prophase and anaphase sections of cell replication.

This results in a decreased amount of "recharged" cohesin being available to regulate gene transcription. Deardorff and team suggest that this results in impaired embryonic development and can give rise to CdLS.

Further analysis of cultured cells with HDAC8 mutations showed that they have a decrease in the amount of cohesin binding to genes compared with cells without these mutations. This effect is similar to that observed for cells with NIPBL mutations.

The team believes that their findings may help with development of possible therapies for CdLS.

"By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS," concluded Deardorff.

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