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Apr 25, 2014

New Human Genetic Brain Disorder Identified

  • Scientists report the discovery of a new human genetic disorder associated with degeneration of the central and peripheral nervous systems. They describe their work (“Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function”) in Cell.

    The findings were generated by two independent but collaborative scientific teams, one based at the Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego (UCSD) School of Medicine, the Academic Medical Center in the Netherlands, and the Yale University School of Medicine.

    The researchers performed DNA sequencing of more than 4,000 families affected by neurological problems. The teams 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, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.

    “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, M.D., Howard Hughes Medical Institute investigator, professor in the UCSD departments of neurosciences and pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UCSD. “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 tested was affected by undiagnosed neurological problems.

    “The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly,” wrote the investigators. “Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing.”

    “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 Josef Penninger, Ph.D., scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.



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