April 25, 2014
Ancient CLP1 Mutation Causes New Genetic Brain Disorder
redOrbit Staff & Wire Reports - Your Universe Online
Scientists have detected a previously unknown neurodegenerative disorder stemming from a single mutation in one lone individual who lived approximately 16 generations ago during the days of the Ottoman Empire in Turkey, according to two studies appearing in Thursday’s edition of the journal Cell. [ 1 ] [ 2 ]
Two international teams of researchers, each of which was performing DNA sequencing of thousands of Turkish children affected by neurological problems, independently discovered that a condition marked by reduced brain size and both sensory and motor defects is caused by a mutation in the gene CLP1.
Murat Gunel, a professor of neurosurgery, genetics and neurobiology at Yale University and senior co-author of one of the two papers, and his colleagues discovered the exact same CLP1 mutation in four apparently unrelated Turkish families.
The discovery of the identical mutation in non-relatives suggested the presence of an ancestral mutation, the researchers explained. The second study, which was completed by researchers from the US and Austria, also found the same CLP1 mutation in 11 children from five additional families with roots tracing back to eastern Turkey.
Children who are affected by the mutation typically suffer from “intellectual disability, seizures, and delayed or absent mental and motor development,” they added. Furthermore, their imaging studies “show atrophy affecting the cerebral cortex, cerebellum, and the brain stem. Analysis of the rare disorder discovered in these subjects could impact how doctors and medical professionals treat more common neurological disorders.
“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,” explained senior study author Josef Penninger of the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences.
“The more we learn about basic mechanisms behind rare forms of neuro-degeneration, the more novel insights we can gain into more common diseases such as Alzheimer's or Lou Gehrig's Disease,” Gunel added. “By dissecting the genetic basis of these neurodevelopmental disorders, we are gaining fundamental insight into basic physiological mechanisms important for human brain development and function.”
The CLP1 protein is involved in generating transfer RNAs (tRNAs), which are molecules that transport amino acids to cellular subunits known as ribosomes, where they are assembled into proteins. Mutations impacting molecules that play a role in tRNA production have previously been implicated in pontocerebellar hypoplasia (PCH) and other neurological conditions in humans, but CLP1’s specific role in human disease had been unknown.
According to Gunel, these unusual recessive genetic neurodegenerative conditions are caused by the prevalence of marriages between closely-related men and women in Turkey and throughout the Middle East. The children of these consanguineous marriages inherit mutations in the same gene from both their mothers and fathers. In other words, unless their parents are closely related, kids are unlikely to inherit two mutations in a single gene.
Image 2 (below): An fMRI scan of the brain of a patient with CLP1 mutation reveals severe atrophy of the brainstem (red line) and cerebellum (blue) as well as lack of formation of the corpus callosum (green), which connects both sides of the cerebrum (yellow), which is also atrophied. The lines outline approximately the expected sizes of the brain areas. A study traced the mutation to a single individual born in Turkey during the Ottoman Empire, some 16 generations ago. Credit: Yale