Genetic link to severe
Scientists in Cambridge have discovered that the loss of a key segment
of DNA can lead to severe childhood obesity. This is the first study to
show that this kind of genetic alteration can cause obesity. The results
are published 6 December 2009 in Nature.
The study, led by Dr Sadaf Farooqi from the University of Cambridge and
Dr Matt Hurles from the Wellcome Trust Sanger Institute, looked at 300
children with severe obesity.
The team scanned each child’s entire genome looking for types of
mutation known as copy number variants (CNVs). CNVs are large chunks of
DNA either duplicated or deleted from our genes. Scientists believe this
type of mutation may play an important role in genetic diseases.
By looking for CNVs that were unique in children with severe obesity,
compared with over 7,000 controls (apparently healthy volunteers from
the Wellcome Trust Case Control Consortium 2), they found that certain
parts of the genome were missing in some patients with severe obesity.
According to Dr Farooqi: “We found that part of chromosome 16 can be
deleted in some families and that people with this deletion have severe
obesity from a young age.
“Our results suggest that one particular gene on chromosome 16 called
SH2B1 plays a key role in regulating weight and also in handling blood
sugar levels. People with deletions involving this gene had a strong
drive to eat and gained weight very easily.”
Dr Matt Hurles adds: “This is the first evidence that copy number
variants have been linked to a metabolic condition such as obesity. They
are already known to cause other disorders such as autism and learning
The findings also have implications for diagnosing severe childhood
obesity, which has on occasion been misattributed to abuse by parents
who have been assumed to be deliberately overfeeding their children and
causing their severe obesity.
“This study shows that severe obesity is a serious medical issue that
deserves scientific investigation,” says Dr Farooqi. “It adds to the
growing weight of evidence that a wide range of genetic variants can
produce a strong drive to eat. We hope that this will alter attitudes
and practices amongst those with professional responsibility for the
health and well-being of children.”
● Citation: Elena G. Bochukova et al. Large, rare chromosomal deletions
associated with severe early-onset obesity. Nature, 6 December 2009
Module of genes affects
By measuring the total gene activity in organs relevant for coronary
artery disease (CAD), scientists at the Swedish medical university
Karolinska Institutet have identified a module of genes that is
important for the recruitment of white blood cells into the
The findings, which are published in the open-access journal PLoS
Genetics, suggest that targeting the migration of white blood cells in
the development of atherosclerosis may help to reduce the risk for
adverse clinical effects such as ischemia and myocardial infarction.
Atherosclerosis is the major cause of myocardial infarction and stroke,
and is responsible for half of all deaths in Western countries.
Complications of atherosclerosis are rapidly increasing as a major cause
of death also in developing countries; the World Health Organisation has
predicted that this will become the number one killer this year.
“It has been an exciting research project, which has gone on for nearly
seven years, involving many different disciplines from thoracic surgeons
to mathematicians,” says team leader Dr. Johan Björkegren at Karolinska
Institutet in Stockholm. “I believe that this kind of clinical study
will follow in the aftermath of the large number of ongoing genomewide
Rather than individual genes or individual DNA variants, the discovery
encompasses a group of 128 functionally related genes in a ‘module’ or
‘network’, which explains their mutual interactions. The involvement of
most of these genes in CAD has not previously been known, but it has
been known that they are involved in endothelial function and
Through the collaboration with Dr Eric Schadt’s team at Washington
University, Seattle, the researchers were also able to take advantage of
previously published genome-wide association studies (GWAS) of CAD to
show that the gene module they have discovered is enriched for inherited
risk of developing myocardial infarction.
“The GWAS are genetic epidemiology studies often involving tens of
thousands of patients and controls, originally designed to link isolated
DNA locus to the risk of developing complex common disorders, such as
atherosclerosis,” says Dr Björkegren. “These studies now need to be
complemented with clinical studies where the patients are also screened
for intermediate molecular phenotypes in disease-relevant organs. The
computational capacities and expertise required to address
simultaneously all molecular activities and their relative
risk-enrichment are available, all that remains is to start recruiting
this kind of cohorts.”
The findings suggest that the severity of atherosclerosis depends on the
rate of the migration of white blood cells from the blood into the
atherosclerotic plaques. Although this pathway is already known to play
a role in atherosclerosis, the Swedish findings suggest that it is the
rate limiting step for disease progression. However, Dr Björkegren
admits that the exact roles of all 128 genes in atherogenesis remain
unexplained. Future studies will focus on understanding the details of
how these genes actually contribute to atherosclerosis in cell cultures
and animal model systems.
● Citation: Hägg et al. Multi- Organ Expression Profiling Uncovers a
Gene Module in Coronary Artery Disease Involving Transendothelial
Migration of Leukocytes and LIM Domain Binding 2: The Stockholm
Atherosclerosis Gene Expression (STAGE) Study. PLoS Genetics, 2009; 5
(12): e1000754 DOI: 10.1371/journal.pgen.1000754
Faulty body clock may make kids
Malfunctioning circadian clock genes may be responsible for bipolar
disorder in children. Researchers writing in the open access journal BMC
Psychiatry found four versions of the regulatory gene RORB that were
associated with paediatric bipolar disorder.
Alexander Niculescu from Indiana University School of Medicine,
Indianapolis, US, worked with a team of researchers at Harvard, UC San
Diego, Massachusetts General Hospital and SUNY Upstate Medical
University to study the RORA and RORB genes of 152 children with the
condition and 140 control children. They found four alterations to the
RORB gene that were positively associated with being bipolar.
Niculescu commented: “Our findings suggest that clock genes in general,
and RORB in particular, may be important candidates for further
investigation in the search for the molecular basis of bipolar
RORB is mainly expressed in the eye, pineal gland and brain. Its
expression is known to change as a function of circadian rhythm in some
tissues, and mice without the gene exhibit circadian rhythm
abnormalities. According to Niculescu: “Bipolar disorder is often
characterised by circadian rhythm abnormalities and this is particularly
true among paediatric bipolar patients. Decreased sleep has even been
noted as one of the earliest symptoms discriminating children with
bipolar disorder from those with attention deficit hyperactivity
disorder (ADHD). It will be necessary to verify our association results
in other independent samples, and to continue to study the relationship
between RORB, other clock genes, and bipolar disorder.”
● Citation: Casey L McGrath et al, Evidence for Genetic Association of
RORB with Bipolar Disorder, BMC Psychiatry 2009,
9:70doi:10.1186/1471-244X-9-70 www.biomedcentral.com/1471- 244X/9/70
Researchers speed up deciphering histone code
A team of Princeton
biologists and engineers has improved the speed and accuracy of
measuring an enigmatic set of proteins that influences almost every
aspect of how cells and tissues function. The new method offers a
long-sought tool for studying stem cells, cancer and other problems of
fundamental importance to biology and medicine.
The research allows scientists an unprecedented look at a special class
of proteins called histones, which are at the core of every chromosome
and control the way instructions in DNA are carried out. Despite rapid
progress in understanding the information encoded in DNA and genes,
scientists have achieved much less insight into the so-called “histone
code”, which determines why a gene in one cell functions differently
than the same gene in another cell.
“We take a cutting-edge approach to a field that has been using more or
less the same techniques for the past 15 years,” said Benjamin Garcia,
assistant professor of molecular biology, who supervised the
experimental aspects of the study.
The technique reduces by a factor of 100 the time it takes to analyse
histones, while requiring far less sample material and achieving much
more nuanced results than existing methods.
The researchers published their results in the October 2009 issue of
Molecular & Cellular Proteomics.
Despite carrying identical DNA, all cells in a body aren't identical - a
cell in the kidney looks and functions very differently from one in the
brain. What makes this specialisation possible is a set of instructions
stored outside of genes or DNA – “epigenetic” information – that helps
each cell adapt to its context. Key players in this process are histones,
tiny protein spindles that the 6- foot-long DNA molecule wraps itself
around in forming a chromosome.
Scientists have long known that histones acquire a variety of small
chemical decorations - small molecules attached here and there along the
length of the histone. The type and location of these add-ons can
regulate nearby genes. Single modifications are known to turn genes on
or off, but what happens when multiple modifications occur in
combinations – the “histone code” – remains a mystery.
The researchers have developed the first practical means to distinguish
between various modified forms of a histone. Under conventional tests
two histones with very different functions could appear identical if
they have the same set of modifications but at different locations on
the molecule. Before now, efforts to distinguish such subtle differences
were extremely difficult and time consuming.
The new shape of DNA
Most of us carry a mental picture of DNA in its iconic form – the famous
double helix unveiled by Francis Crick and James Watson. But researchers
are beginning to develop a new picture of DNA that shows the molecule’s
more dynamic side, which is capable of morphing into a large number of
complex shapes. This shape-shifting ability permits proteins to attach
and read the right region of DNA so genes can be turned on or off at the
The findings show that proteins are adept at reading nuances in the
shape of the double helix. Those variations in shape transmit
information about where proteins need to bind to make sure the right
genes are activated or silenced during development.
“The ideal double helix should not be viewed as a rigid entity but
rather seen as a first approximation to a large set of more complex
shapes that are recognised by proteins so as to bind to DNA in a
sequencespecific fashion,” said Barry Honig, Howard Hughes Medical
Institute investigator at Columbia University.
Honig and his colleagues have discovered a new mechanism by which
proteins recognise specific regions of DNA. Their research is reported
in the October 29, 2009, issue of the journal Nature.
Scientists have long known that specialised DNA-binding proteins, such
as transcription factors that activate and repress genes, look for their
docking sites on DNA by scanning the genome for a specific nucleotide
sequence that says “bind here”. When proteins recognise that sequence,
they bind to DNA and begin to do their jobs. But over the last 20 years,
researchers have accumulated evidence that the physical shape of DNA can
also influence where and when proteins attach to DNA.
The new studies published in Nature by Honig and his colleagues extend
those results and describe a new recognition strategy that proteins use
to identify and bind to DNA. The coiled, complementary strands of DNA
form ‘major’ and ‘minor’ grooves, to which proteins can bind.
“The question for us was, why is that important?” Honig says. “What we
showed is that the electrostatic potential of the DNA – which is used to
attract positive charges – is stronger when a groove is narrow.”
They found that narrow minor grooves tended to attract parts of the
protein that contained the amino acid arginine, which is positively
charged. They saw that there are many arginine binding sites in DNA that
have narrower minor grooves and that these have more negative
electrostatic potentials that attract positively charged regions of
“The proteins are actually reading the shape of the DNA through its
effect on electrostatic potential,” Honig says. “Sequence determines
shape, which determines the affinity for arginines – a mechanism made
possible because DNA does not form a perfect double helix.”
Modified stem cell therapy cures
adult sickle cell disease
A modified blood adult stemcell transplant regimen has effectively
reversed sickle cell disease in nine of 10 adults who had been severely
affected by the disease, according to results of a US National
Institutes of Health study in the 10 December issue of the New England
Journal of Medicine.
“This trial represents a major milestone in developing a therapy aimed
at curing sickle cell disease,” said NIDDK Director Griffin P. Rodgers
M.D., a co-author of the paper. “Our modified transplant regimen changes
the equation for treating adult patients with severe disease in a safer,
more effective way.”
In trials by other investigators, nearly 200 children with severe sickle
cell disease were cured with bone marrow transplants after undergoing a
regimen in which their own marrow was completely destroyed with
chemotherapy. That regimen, however, had proven too toxic for adults,
who have years of accumulated organ damage from the disease and are less
able to tolerate complete marrow transplantation.
In contrast to the established method in children, this adult trial
sought to reduce toxicity by only partially replacing the bone marrow.
The much longer lifespan of normal red blood cells, compared to sickle
red blood cells, allows the healthy cells to outlast and completely
replace the diseasecausing cells.
To achieve this goal, the investigators used a low dose of radiation to
the whole body and two drugs, alemtuzumab and sirolimus, to suppress the
immune system. Alemtuzumab depletes immune cells, but does not adversely
affect blood stem cells. Sirolimus does not block the activation of
immune cells, but inhibits their proliferation, creating a balance that
potentially helps prevent rejection of the new stem cells.
The radiation favorably conditions the bone marrow, where donor stem
cells move in and begin producing new, healthy red blood cells. After a
median two and a half years follow-up, all 10 recipients were alive and
sickle cell disease was eliminated in nine.
“Remarkably, the treatment did not result in graft-versushost disease (GVHD)
for any of the participants,” noted Susan B. Shurin, MD, acting director
of the NHLBI. GVHD is a common complication of stem cell transplantation
and can lead to serious problems, such as rash, diarrhea and nausea,
liver disease, or death. “We are continuing to explore better treatments
with fewer side effects to help the millions of sickle cell patients
worldwide. This is a very important study because it lessens the
toxicity of a therapy known to be highly effective.”
Stem cells used to treat eye disease
Newly published research, by investigators, at the North East England
Stem Cell Institute (NESCI) in the journal Stem Cells reported the first
successful treatment of eight patients with “Limbal Stem Cell
Deficiency” (LSCD) using the patients’ own stem cells without the need
of suppressing their immunity.
LSCD is a painful, blinding disease that requires long-term, costly
treatment with frequent clinic visits and intensive hospital admissions.
The vision loss due to LSCD makes this disease not only costly, but
often requires social support due to the enormous impact on a patient’s
quality of life. This is further magnified by the fact that LSCD mostly
affects young patients.
Dr Francisco Figueiredo, a member of the NESCI team, said: “Corneal
cloudiness has been estimated to cause blindness in eight million people
(10% of total blindness) worldwide each year. A large number of ocular
surface diseases, both acquired and congenital, share features of
partial or complete LSCD.”
He added that chemical burns to the eye were the most common cause of
Professor Lako, another member of the NESCI team, said: “This study
demonstrates that transplantation of cultured corneal stem cells without
the use of animal cells or products, is a safe and effective method of
reconstructing the corneal surface and restoring useful sight in
patients with unilateral LSCD.
He added that this research shows promise to help hundreds of people
regain their sight and offers a new treatment for people with LSCD.
Professor Michael Whitaker FMedSci, Co-Director of NESCI, which is a
collaboration between Durham and Newcastle Universities, Newcastle NHS
Foundation Trust and other partners, said: “Stem cells from bone marrow
have been used successfully for many years to treat cancer and immune
disease, but this is the first successful stem cell therapy using stem
cells from the eye without animal products to treat disease. Because the
early results look so promising, we are thinking hard now about how to
bring this treatment rapidly into the clinic as we complete the
necessary clinical trials.”
A larger study involving 24 new patients is currently underway with
funding from the UK’s Medical Research Council.
● Citation: Kolli S,
Ahmad S, Lako M, Figueiredo F, “Successful clinical implementation of
corneal epithelial stem cell therapy for treatment of unilateral limbal
stem cell deficiency”, STEM CELLS, 2009, DOI: 10.1002/stem.276