The discovery of this genetic disorder, reported in two papers in
the journal Cell, demonstrates the growing power of new tools to
uncover the causes of diseases that previously stumped doctors.
Besides bringing relief to affected families, who can now go through
prenatal genetic testing in order to have children without the
disorder, the discovery helps lend insight into more common
neurodegenerative disorders, such as ALS, also known as Lou Gehrig's
disease, the researchers said.
The reports come from two independent teams of scientists, one led
by researchers at Baylor College of Medicine and the Austrian
Academy of Sciences, and the other by Yale University, the
University of California, San Diego, and the Academic Medical Center
in the Netherlands.
Both focused on families in Eastern Turkey where marriage between
close relatives, such as first cousins, is common. Geneticists call
these consanguineous marriages.
In this population, the researchers focused specifically on families
whose children had unexplained neurological disorders that likely
resulted from genetic defects.
Both teams identified a new neurological disorder arising from a
single genetic variant called CLP1. Children born with this disorder
inherit two defective copies of this gene, which plays a critical
role in the health of nerve cells.
Babies with the disorder have small and malformed brains, they
develop progressive muscle weakness, they do not speak and they are
increasingly prone to seizures.
Dr Ender Karaca, a post-doctoral associate in the department of
molecular and human genetics at Baylor, first encountered the
disorder in 2006 and 2007 during his residency training as a
clinical geneticist in Turkey.
"We followed them for years," said Karaca, a lead author on one of
the papers. Karaca said he and his colleagues performed some basic
genetic tests on the families but to no avail.
He presented these cases at a genetics conference in Istanbul in
2010, where he caught the attention of Dr James Lupski, who leads
the Center for Mendelian Genomics at Baylor, a joint program with
the Johns Hopkins University School of Medicine funded by the
National Human Genome Research Institute (NHGRI).
The center is focused on finding and recruiting thousands of
patients and families with undiagnosed disease likely caused by
single-gene defects known as Mendelian disorders.
Lupski recruited Karaca into his program at Baylor, where the team
continued to work on identifying more cases. A broad genetic test
known as exome sequencing, which looks at all of the protein-making
genes representing about 1 percent of the genetic code, eventually
identified five families with similar characteristics and the same
Researchers needed confirmation in lab tests that the defect could
cause the neurological problems seen in the families. That came at a
meeting in Vienna, when Dr Richard Gibbs, director of Baylor's Human
Genome Sequencing Center, presented the gene as part of a list of
suspected disease-causing variants.
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In the audience was Dr Josef Penninger of the Austrian Academy of
Sciences in Vienna, whose lab had been working on a model of this
same genetic variant in mice.
Both the mice and the people with
the genetic defect shared similar characteristics. Further
experiments by the Vienna team showed the mutant copies of the CLP1
gene affected the survival of key cells in the brain stem of the
"We had patients with an interesting phenotype (symptoms) and a
novel gene but no evidence from the lab that these mutations are
disease-causing. They had a model organism, a mouse, but they didn't
have evidence that it affected people. It was a perfect storm," said
Baylor geneticist Dr Wojciech Wiszniewski, author of another study.
As the Baylor-led researchers were working on the problem,
collaborators at the Yale Center for Mendelian Genomics, another of
the government-funded Centers for Mendelian Genomics, were
sequencing families in Turkey under the direction of Dr Murat Gunel,
a professor of genetics and neurobiology at Yale.
Gunel and colleague Dr Joseph Gleeson at University of California,
San Diego, have been focusing on understanding the fundamental
mechanisms of how the human brain develops.
Gunel had been collecting DNA samples from children affected with
neurodevelopmental brain problems. The team did exome sequencing on
more than 2,000 samples, and they, too, turned up a disorder linked
with the CLP1 gene.
Further investigation of the genetic data suggested that all of the
cases they identified among four, unrelated families were linked
with a single, spontaneous mutation in the CLP1 gene that occurred
16 generations, or about 400 years ago.
Gunel, who received his medical degree in Istanbul, said the high
rates of marriages between closely related people in Turkey and the
Middle East lead to these rare disorders as affected children
inherit mutations in the same gene from both of their parents.
Without such marriages, children are very unlikely to inherit two
mutations in the same gene.
The Yale paper credits Lupski at Baylor for sharing some of his
unpublished findings. Gibbs said the whole effort is an "good
example of communication-driven discovery."
(Reporting by Julie Steenhuysen)
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