Fig. 1: Magnetic resonance imaging shows the brain of a normal subject (top left) and an ARCL patient with a mutation in PYCR1 (top right), where there are clear defects in the corpus callosum (the structure linking the brain hemispheres). Bottom panels show expression levels of PYCR1 (green) in skin cells from each subject.
© 2009 A*STAR
Wrinkled skin and weakened bones might be taken as normal symptoms of aging, but patients suffering from the various hereditary ‘progeriatric’ disorders classified as autosomal recessive cutis laxa (ARCL) start to experience these effects early in childhood. The clinical similarity of different ARCL subtypes makes them difficult to classify accurately and little is known about their genetic bases.
An aggressive research environment led Bruno Reversade and his team at A*STAR’s Institute of Medical Biology in Singapore to join forces with direct competitor Stefan Mundlos of the Charité Universitaetsmedizin in Berlin, Germany. “Having come from the developmental biology field, I found human genetics to be significantly more competitive,” says Reversade. “We both thought that we stood a better chance together than against one another.”
Their collaboration paid off, and their study of individuals from 15 closely related ARCL-affected families led to the identification of a small segment of chromosome 17 that appeared to be linked to the disease. Upon closer analysis of this region, the gene encoding Δ1-pyrroline-5-carboxylate reductase 1 (PYCR1) emerged as the likely culprit, which has numerous mutations apparent exclusively in affected individuals.
PYCR1 is highly expressed in skin and bones, and reduced levels of this protein were noted in skin cells from a number of patients. The investigators found that PYCR1 is localized to the mitochondria—a focal point for cell metabolism—where it participates in synthesis of the amino acid proline, but also acts as an apparent bulwark against cellular damage. Exposure to highly oxidative conditions causes cells to produce molecules called ‘reactive oxygen species’ (ROSs), which act as triggers for cell death, but PYCR1 appears to counter oxidative stress by keeping ROS production at bay. When Reversade and his colleagues knocked out the equivalent gene in frog embryos, they noticed severe developmental defects—most notably in the blood and skin. As expected, these defects apparently resulted from increased cell death in these tissues, demonstrating the usefulness of this simpler animal model for ARCL.
Pairing of this cellular-level analysis with existing pathological data suggested that defects in this pathway could underlie several ARCL disease subtypes. “It was surprising that such a seemingly trivial metabolic pathway can have such a profound effect on human aging,” says Reversade. He adds that findings showing that proline levels are unaffected by PYCR1 mutation—but that brain development apparently is (Fig. 1)—reveal a surprisingly interesting role for this ‘dull’ enzyme. “There is much more here than meets the eye,” he concludes.
The A*STAR-affiliated authors in this highlight are from the Institute of Medical Biology.
