Adolescent idiopathic scoliosis—a condition
featuring curvature of the spine—affects tens of
millions of children worldwide, but does not have a
known cause.
Now, scientists at the RIKEN Center for Integrative
Medical Sciences in collaboration with Keio
University in Japan have discovered a gene that is
linked to susceptibility to the condition. Published
in the American Journal of Human Genetics, the work
details how the susceptibility gene is associated
with increased expression of the protein BNC2, which
is in turn regulated by another protein called YY1.
Adolescent idiopathic scoliosis - Credit: Nevit
Dilmen
“AIS is a complex and mysterious disease with
awkward spinal deformities that can be a nightmare
for affected people,” explains team leader Shiro
Ikegawa. “We were excited to find a single
nucleotide polymorphism located on human chromosome
number nine that is significantly associated with
the disease.”
The discovery began with a genome-wide association
study using more than ten thousand volunteers with
and without scoliosis. This type of study looks for
small differences in genes—called single nucleotide
polymorphisms, or SNPs—that occur more frequently in
people with a certain disease.
After confirming the association between a
particular SNP (pronounced “snip”) in two additional
independent populations—one in Japan and one in
China—they determined that it is located near the
part of the DNA that codes for the protein BNC2.
The team then examined where BNC2 is expressed in
humans. Using quantitative RT-PCR, they found that
it is most highly expressed in the uterus, spinal
cord, bone, and cartilage. “This result told us that
we were on the right track,” says Ikegawa, “and
evidence that the SNP variation associated with the
disease led to higher levels of BNC2 expression told
us that this SNP has the potential to regulate
expression of BNC2.”
The team tested this hypothesis and found that not
only was BNC2 expression triggered by the protein
YY1—which binds to the DNA around the SNP—but that
for genes with the at-risk SNP variant, the amount
of BNC2 produced when YY1 was present was much
greater than for genes with the non-risk variant.
The BNC2 gene is highly conserved across diverse
species, and plays roles in a variety of tissues. To
test how over-expression of BNC2 affects
development, the team expressed it in zebrafish
embryos and found that it resulted in severe body
curvature that was positively correlated to the
amount of BNC2.
These results and the abundance of BNC2 in the human
spine and bones make it likely that adolescents with
the disease-associated SNP variant may begin to
produce excess BNC2 at puberty if other genetic or
environmental factors are also present.
The next step is to understand how BNC2 causes
scoliosis and why it is so much more prevalent in
women than in men. “The expression of BNC2 in the
uterus and changes that occur during puberty could
help explain the large sex difference,” explains
Ikegawa. “Additionally, knowing what genes are
downstream of BNC2 will provide us with potential
targets for therapeutic interventions.”
For more information
Yoji Ogura, Ikuyo Kou, Shigenori Miura, Atsushi
Takahashi, Leilei Xu, Kazuki Takeda, Yohei
Takahashi, Katsuki Kono, Noriaki Kawakami, Koki Uno,
Manabu Ito, Shohei Minami, Ikuho Yonezawa, Haruhisa
Yanagida, Hiroshi Taneichi, Zezhang Zhu, Taichi
Tsuji, Teppei Suzuki, Hideki Sudo, Toshiaki Kotani,
Kota Watanabe, Naobumi Hosogane, Eijiro Okada,
Aritoshi Iida, Masahiro Nakajima, Akihiro Sudo,
Kazuhiro Chiba, Yuji Hiraki, Yoshiaki Toyama, Yong
Qiu, Chisa Shukunami, Yoichiro Kamatani, Michiaki
Kubo, Morio Matsumoto, Shiro Ikegawa, "A functional
SNP in BNC2 is associated with adolescent idiopathic
scoliosis", American Journal of Human Genetics,
doi: 10.1016/j.ajhg.2015.06.012
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