The basic biology of Roberts syndrome

Children born with developmental disorders called cohesinopathies can suffer severe consequences, including intellectual disabilities, limb shortening, craniofacial anomalies, and slowed growth. Cohesinopathies result from mutations in genes encoding cohesins and the factors that regulate their function. Cohesins form ring-shaped protein complexes that help organize the genome. Although researchers know which mutations underlie some cohesinopathies, little is known about the resulting disruption of downstream signals.

Recently, Investigator Jennifer Gerton, PhD, reported that mTOR signaling, a prominent signaling pathway that drives cell growth, is inhibited in the cohesinopathy known as Roberts syndrome (RBS). That work, which analyzes patient cells and zebrafish models of RBS, shows that jump-starting the sluggish signaling pathway with the amino acid L-leucine partially rescues defects associated with the disease at both the cellular and organismal level.

Gerton is encouraged but cautious about these findings. “Use of a nontoxic, inexpensive amino acid to treat human disease could be of benefit,” she says, noting that L-leucine dietary supplementation is being tested in clinical trials for Diamond-Blackfan anemia, a genetic disorder. “Many aspects of RBS are unlikely to respond to postnatal leucine treatment, but leucine supplementation might improve some disease manifestations in RBS.”

RBS is a rare cohesinopathy, but a related condition called Cornelia de Lange syndrome (CdLS) occurs more frequently—about one in 10,000 live births. Researchers have defined
mutations causing CdLS, and CdLS zebrafish models are also available. In fact, Gerton recently received a grant from the
Cornelia de Lange Syndrome Foundation to assess the effect of L-leucine supplementation in those fish (related story).

The study was published in the October 2013 issue of PLoS Genetics.