NEW YORK (GenomeWeb) – Research by two independent groups reporting in Cell this week has revealed a new brain disorder that can be traced back to mutations in the RNA kinase coding gene CLP1.
The condition resembles a set of brain disorders known as pontocerebellar hypoplasias, which also stem from RNA-related problems that lead to progressive brain degeneration during infancy. But the new studies mark the first time that CLP1 has been implicated in such a syndrome.
An international team led by investigators at the Baylor College of Medicine and the Austrian Academy of Sciences' Institute of Molecular Biotechnology got wind of the CLP1-associated condition while working with 11 individuals with brain malformation, atypical facial features, a propensity for seizures, and related nervous system symptoms.
Following brain structure scans, motor skill assessments, and other tests that pointed to the presence of a potential neurological syndrome, the researchers did whole-exome sequencing on four affected individuals from two families.
An analysis of the exome sequence data revealed an amino acid sequence altering change in the chromosome 11 gene CLP1 that has not been described in variant databases or in data from the 1000 Genomes Project or the National Heart, Lung, and Blood Institute Exome Sequencing Project.
But the mutation did turn up in members of three more families when the team did targeted CLP1 sequencing on individuals sharing central and peripheral nervous system characteristics with those who carried the CLP1 glitch.
The researchers' follow-up experiments, including experiments in mice, indicated that the newly detected mutation acts to alter interactions of the RNA kinase enzyme encoded by CLP1.
Consequently, they reported, the mutated version of the kinase can no longer work with a transfer RNA splicing endonuclease complex (TSEN), prompting a drop in tRNA splicing that ultimately affects the survival of brain cell progenitors and other brain features.
Researchers from the US, Netherlands, and elsewhere linked the same CLP1 mutation to tRNA splicing, tRNA maturation, and cell survival defects in their own study of individuals with brain disorder and neurodegeneration.
That team initially saw the CLP1 change during an exome sequencing stage of the study that included more than 2,000 consanguineous families affected by neurological or neurodegenerative conditions that manifested themselves in childhood.
When they examined exome sequence data for representatives from these families, the investigators identified the CLP1 mutation in members of four Turkish families affected by comparable neurodegenerative conditions.
In both new papers, researchers described tracing the CLP1 change back to a founder mutation events occurring many generations ago.
Though rare overall, the teams were able to find and characterize the brain condition by focusing on families with known or suspected consanguinity, which made it more likely that children might carry the same rare change to CLP1 on both copies of the gene.
"[T]his is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features," the University of California at San Diego's Joseph Gleeson, co-corresponding author on the second study, said in a statement.
"Once we had the gene spotted in these total of seven families, then we could see the common features," Gleeson added. "It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced."