New Genetic Brain Disorder Found in Humans

By performing DNA sequencing of more than 4,000 families affected by neurologic difficulties, the two teams of investigators independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1 (cleavage and polyadenylation factor I), which is known to regulate tRNA metabolism in cells.

The news findings were reported in the April 24, 2014 issue of the journal Cell. The findings were made by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine (Houston, TX, USA) and the Austrian Academy of Sciences (Vienna, Austria), the other at the University of California (UC), San Diego School of Medicine (USA) , the Academic Medical Center (AMC; Amsterdam, The Netherlands), and Yale University School of Medicine (New Haven, CT, USA).

Clues into this rare disorder, according to the researchers, may have important implications for the future treatment of more common neurologic disorders. “What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features,” said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of neurosciences and pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego. “Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced.”

Each child assessed was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, collaborated with James R. Lupski, MD, PhD, of the Baylor College of Medicine.

“Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig’s disease,” said Dr. Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.

These scientists performed DNA sequencing on children with neurologic difficulties. Seven out of the more than 4,000 families studied shared an identical CLP1 mutation, which was associated with seizures, motor defects, speech impairments, brain atrophy, and neuronal death.

Dr. Bass, from the AMC, noted that the neurological condition represents a new form of PCH. “Identification of yet another genetic cause for this neurodegenerative disorder will allow for better genetic testing and counseling to families with an affected child,” he said.

In a published paper in 2013, Dr. Gleeson and colleagues identified a different gene mutation for a particularly severe form of PCH, and reported early evidence that a nutritional supplement might one day be able to prevent or reverse the condition.

Related Links:
Baylor College of Medicine
Austrian Academy of Sciences
University of California, San Diego School of Medicine