| September 25,
Danger on Chromosome 15 - Unstable
Region Yields Genes for Prader-Willi/Angelman Syndromes
and Spastic Paraplegia
(Philadelphia, PA) - While it might
have given our ancestors an evolutionary advantage,
an "unstable" region on human chromosome 15 is also
the source of a set of inherited neurological diseases.
Researchers at the University of Pennsylvania School
of Medicine discovered four new genes normally found
on chromosome 15 that, when lost, may contribute to
Prader-Willi and Angelman syndromes. Subsequently, the
researchers were able to determine that the mutation
of one these four genes, NIPA1, is also responsible
for a hereditary disease called spastic paraplegia.
Their findings make genetic screenings and drug development
for spastic paraplegia possible and can open the door
for better diagnosis of chromosome 15 rearrangements,
including deletions that cause Prader-Willi and Angelman
syndromes, and duplications found in some cases of autism.
"Genes located in this part of chromosome 15 sit among
a lot of genetic flotsam and duplicated regions we refer
to as breakpoint regions. In the grand scheme of things,
this is an evolutionary plus for humans, as these regions
are prone to genetic recombination, duplication and
other forms of gene shuffling that can add diversity
to the human genome in the process of passing down chromosomes,"
said Robert D. Nicholls, D. Phil, a Professor
in Penn's Departments of Psychiatry and Genetics. "In
individuals, however, it can cause disease."
Nicholls and his colleagues announce their findings
in two separate papers in the October issue of the American
Journal of Human Genetics (available now online). The
first paper describes how breakpoint regions on human
chromosome 15 contribute to chromosome rearrangements
in evolution and Prader-Willi and Angelman syndromes,
and identifies four new genes - named NIPA1, NIPA2,
CYFIPI, and GCP5 - in the most unstable part of chromosome
15. The second paper details how researchers linked
a mutation in NIPA1 to families with hereditary spastic
"What we see here is two very important ways in which
genetics can effect disease," said Nicholls. "Often
inherited disease can stem from the mutation of a single
gene, such as NIPA1 in spastic paraplegia. In the case
of chromosome 15, disease can be caused by rearrangements
such as occurs in Prader-Willi and Angelman. These are
simply good genes in a bad neighborhood."
Scientists have known that Prader-Willi and Angelman
can be attributed to the disruption of genes that sit
near breakpoints - regions in the chromosome that are
prone to being re-arranged by the cell's genetic machinery
before the chromosomes are passed to their offspring.
Prader-Willi and Angelman syndromes occur in one in
every 12,000 to 15,000 births.
The two syndromes are genetically-related - yet separate
- neurological disorders whose effects are determined
based on which parent donates the faulty chromosome.
Prader-Willi occurs when the chromosome is inherited
from the father, and features mild cognitive impairment
and morbid obesity; while Angelman is inherited from
the mother, and is characterized by seizures, movement
disorders, and severe mental retardation. Unlike the
major genes associated with the two disorders, the function
of the four genes discovered in the Nicholls lab are
not dependent on which parent donated the chromosome.
"These are complex disorders that, because of these
chromosomal breakpoints, don't play by the normal rules
of genetics," said Nicholls. "The loss of these four
genes on one chromosome may modify Prader-Willi and
Angelman, but we still don't know exactly how."
Nicholls realized that one of these four genes might
also make a good candidate for the cause of spastic
paraplegia, a hereditary condition marked by the progressive
development of leg paralysis, which had also been mapped
to this 'dangerous' region on chromosome 15.
The Penn researchers collaborated with John K. Fink,
MD, a neurologist with the University of Michigan Health
System and noted researcher of spastic paraplegia. Fink's
laboratory was able to provide small DNA samples from
several individuals of a family with spastic paraplegia
and, of the four genes identified, Dr. Jing-Hua Chai
in the Nicholls' laboratory first identified a NIPA1
gene mutation solely in individuals with spastic paraplegia.
The Michigan laboratory completed the mutation screening
and independently identified an identical mutation in
a second family with spastic paraplegia. Altogether,
these findings can expand the genetic diagnosis of the
disease, before clinical onset as well as for families
who wish to seek prenatal genetic counseling.
Funding for this research was provided through grants
from the National Institutes of Health, the March of
Dimes Birth Defects Foundation, and the Muscular Dystrophy
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Editor's Note: Editor's Note: You
can also find the American Journal of Human Genetics
online at: http://www.journals.uchicago.edu/AJHG/journal/rapid.html
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