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Novel mechanism for neurological disorder unraveled by international team

Date:
April 24, 2014
Source:
Baylor College of Medicine
Summary:
A novel gene (CLP1) associated with a neurological disorder affecting both the peripheral and central nervous systems has been discovered by an international team of researchers. They show that disturbance of a very basic biological process, tRNA biogenesis, can result in cell death of neural progenitor cells. This leads to abnormal brain development and a small head circumference as well as dysfunction of peripheral nerves.

A team of international scientists led by Baylor College of Medicine has discovered a novel gene (CLP1) associated with a neurological disorder affecting both the peripheral and central nervous systems. Together with scientists in Vienna they show that disturbance of a very basic biological process, tRNA biogenesis, can result in cell death of neural progenitor cells. This leads to abnormal brain development and a small head circumference as well as dysfunction of peripheral nerves.

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The study published today in the current issue of the journal Cell.

"This is the first human disorder associated with the gene CLP1," said Dr. Ender Karaca, post-doctoral associate in the department of molecular and human genetics at Baylor.

The gene find is significant because CLP1 has a role in RNA processing and has important implications for genomic approaches to Mendelian disease and for our understanding of human biology and brain development, Karaca said.

Karaca's work with families of this rare disorder began many years ago during his residency training as a clinical geneticist in Turkey.

A chance meeting with Dr. James R. Lupski, the Cullen Professor and Vice Chair of Molecular and Human Genetics and professor of pediatrics at Baylor, at a medical meeting in Istanbul, Turkey would lead to Karaca's recruitment as a trainee in Lupski's lab where the research took off and eventually the team unveiled new clues about the genetic malfunction that may be causing the disorder in these families.

Lupski leads the Center for Mendelian Genomics at Baylor, a joint program with the Johns Hopkins University School of Medicine that is funded by the National Human Genome Research Institute. The Center is focused on advancing research of the cause of rare, single-gene diseases usually called Mendelian disorders.

Using whole exome sequencing (a next generation test to analyze the exons or coding regions of thousands of genes simultaneously) conducted at the Baylor College of Medicine Human Genome Sequencing Center, the researchers identified CLP1 mutations in two unrelated families with the disorder.

The two families had distinct facial dysmorphic features that led Karaca to identify the gene in three additional families with very similar features.

"With the first families, we had no idea what gene might be causing this disorder, so we did a genome analysis and a good candidate gene screen came in with CLP1," said Karaca.

Based on his clinical knowledge of brain formation, he identified three additional families with very similar clinical and radiological features as the two families with confirmed CLP1 mutations.

"This time we sequenced the families for this specific CLP1 gene mutation and all had it," said Karaca.

But the identification of the mutation also brought new questions for the researchers that caused them to dig deeper into the gene.

"In all four families there were a total of eight people affected and now the problem is they all have the same gene mutated but one variant," said Lupski, the corresponding author of the report. "Ideally, we would have four families with the same gene but multiple types of mutations. This is sort of a polymorphism (a variation of unknown significance), so we started to think about other ways to obtain experimental evidence to support that this mutation was causative for the disease by doing functional studies on the variant."

Another chance encounter between Dr. Richard Gibbs, director of the Human Genome Sequencing Center at Baylor, and Dr. Josef Penninger, scientific director of IMBA, the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna, who had a lot of interest already in CLP1 -- and a mouse model to test new experiments with the gene -- led to further discoveries of the importance of this gene.

"Penninger's mouse model had shown some of the similarities of the patients in the study with regard to the peripheral nervous system, but they had not identified brain malformation or small heads," said Lupski. "But when we showed them our patient data, they went back very carefully and looked, and indeed showed these same features."

It is remarkable that we used patient clinical information to enhance research and help guide experimental investigations then conducted in Vienna in their mouse model, said Lupski.

Penninger's team then could experimentally manipulate their animal model and further characterize this rare disease. "They answered key questions, and it became clear that this is not just a brain disease or a peripheral nerve disease; in fact, this spoke to some kind of neural stem cell progenitor problem," said Lupski. "The Vienna team of Dr. Javier Martinez, also a co-corresponding author on the study, could actually show that mutations in CLP1 affect tRNA biogenesis and that CLP1 mutant brain stem cells become more apoptotic (invoking cell death). The idea of neural progenitor or stem cell susceptibility to cell death may be a conceptual leap in the mechanism for a host of neurological disorders," said Lupski.

The invocation of cell death in this disorder would explain the clinical feature, the small heads caused by loss of nerve cells in the brain, the team found.

"This is a new way of thinking in the neurobiology field," said Lupski. "Basically it is a mutation that makes potential stem cells, or precursor cells, susceptible to apoptotic cell death pathways. So we have to start thinking about lots of diseases that might fall into this category, for example ALS (Lou Gehrig's disease)."

"As the Baylor-Johns Hopkins Center for Mendelian Genomics enters year three of our four year grant, we have found new learning opportunities with each phenotype," said Shalini Jhangiani, senior project manager in the Human Genome Sequencing Center and a co-author on the study. "To date we have over 350 phenotypes enrolled in our study with over 3,200 patient samples having undergone exome sequencing. The CLP1 story has raised expectations for future collaborative studies."


Story Source:

The above story is based on materials provided by Baylor College of Medicine. The original article was written by Glenna Picton. Note: Materials may be edited for content and length.


Journal Reference:

  1. Ender Karaca, Stefan Weitzer, Davut Pehlivan, Hiroshi Shiraishi, Tasos Gogakos, Toshikatsu Hanada, ShaliniN. Jhangiani, Wojciech Wiszniewski, Marjorie Withers, IanM. Campbell, Serkan Erdin, Sedat Isikay, LuisM. Franco, Claudia Gonzaga-Jauregui, Tomasz Gambin, Violet Gelowani, JillV. Hunter, Gozde Yesil, Erkan Koparir, Sarenur Yilmaz, Miguel Brown, Daniel Briskin, Markus Hafner, Pavel Morozov, ThaliaA. Farazi, Christian Bernreuther, Markus Glatzel, Siegfried Trattnig, Joachim Friske, Claudia Kronnerwetter, MatthewN. Bainbridge, Alper Gezdirici, Mehmet Seven, DonnaM. Muzny, Eric Boerwinkle, Mustafa Ozen, Tim Clausen, Thomas Tuschl, Adnan Yuksel, Andreas Hess, RichardA. Gibbs, Javier Martinez, JosefM. Penninger, JamesR. Lupski. Human CLP1 Mutations Alter tRNA Biogenesis, Affecting Both Peripheral and Central Nervous System Function. Cell, 2014; 157 (3): 636 DOI: 10.1016/j.cell.2014.02.058

Cite This Page:

Baylor College of Medicine. "Novel mechanism for neurological disorder unraveled by international team." ScienceDaily. ScienceDaily, 24 April 2014. <www.sciencedaily.com/releases/2014/04/140424125132.htm>.
Baylor College of Medicine. (2014, April 24). Novel mechanism for neurological disorder unraveled by international team. ScienceDaily. Retrieved October 24, 2014 from www.sciencedaily.com/releases/2014/04/140424125132.htm
Baylor College of Medicine. "Novel mechanism for neurological disorder unraveled by international team." ScienceDaily. www.sciencedaily.com/releases/2014/04/140424125132.htm (accessed October 24, 2014).

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