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A team of researchers from RCSI, the Alpha One
Foundation and Harvard University made a major
breakthrough in identifying a significant proportion of
the population who have an increased risk of developing
chronic obstructive pulmonary disease (COPD), a
debilitating lung condition, due to a combination of
inherited genes and exposure to cigarette smoke.
What it means for human health:
Individuals who are deficient in alpha-1 antitrypsin (AAT),
a protein which protects the lungs, are at increased risk of
developing COPD. The normal AAT gene is called M, and the
faulty AAT gene is called Z. We inherit two copies of every
gene, one from each parent, and the majority of individuals
inherit two normal M AAT genes and are known as MM.
Until recently it was thought that people had to inherit the
abnormal Z AAT gene from both parents to have a risk of
COPD. It remained unclear whether MZ individuals who
carry one normal AAT gene (M) and one abnormal AAT gene
(Z) also had a risk. Researchers from RCSI's Department of
Medicine evaluated this question using a unique approach by
examining the first degree MM (unaffected) and MZ relatives
of MZ carriers with a diagnosis of COPD, thus avoiding bias
in patient selection. Almost 250 individuals were studied.
All were tested for AAT deficiency, had lung function tests
and completed a lung health questionnaire. This study
showed definitively that MZ people who smoke had worse
lung function than smokers with no abnormal Alpha-1 genes
(MM individuals). Smoking MZs had an estimated five- to
10-fold increased risk of developing COPD compared to
MM individuals. MZs who don't smoke had no increased risk.
There are approximately 200,000 MZ individuals in Ireland
and about eight million in the United States.
The paper: Clarification of the risk of chronic obstructive
pulmonary disease in
1-antitrypsin deficiency PiMZ
heterozygotes. American Journal of Respiratory and
Critical Care Medicine, 2014 February 15, 189:419-27.
The authors: Molloy K, Hersh CP, Morris VB, Carroll TP,
O'Connor CA, Lasky-Su JA, Greene CM, O'Neill SJ,
Silverman EK, McElvaney NG.
RCSI researchers and collaborators identified a novel
gene for epilepsy along with a novel biological pathway
involved with the condition.
What it means for human health:
A particular gene called topoisomerase II (TOP2)
facilitates DNA cutting, binding and winding, which
is critical for allowing particular genes and associated
proteins to be expressed. TOP2 normally repairs any cuts
it makes in DNA but on occasion they remain unrepaired.
In this work, the authors identify mutations in a gene
called tyrosyl DNA phosphodiesterase-2 (TDP2) which
codes for an enzyme that repairs any breaks in DNA that
TOP2 leaves behind. The mutations were discovered in
individuals with intellectual disability, seizures and ataxia.
Through experiments on cells from the patients and other
experimental models, the team illustrated that properly
functioning TDP2 is required for the normal expression
of many genes, including numerous genes associated
with neurological function and/or disease. Collectively,
this work shows that TDP2 is critical to normal neuronal
development and maintenance. If mutations interrupt the
functioning of TDP2, it can lead to abnormal neuronal
development, causing learning disability and seizures.
The paper: TDP2 protects transcription from abortive
topoisomerase activity and is required for normal neural
function. Nature Genetics, 2014 May, 46:516-21. Authors:
Cavalleri G, McCormack M, Delanty N.
New gastroenterology research carried out by RCSI in
conjunction with Trinity College Dublin and Johns Hopkins
University in Baltimore, Maryland, uncovered a new route
for the development of anti-diarrhoeal drugs. The new
route directly targets cells and molecular processes that
control water movement into the intestine and may help
with the development of a new class of anti-diarrhoeal
What it means for human health:
Diarrhoeal diseases, such as irritable bowel syndrome
and inflammatory bowel disease, are common in Western
societies and represent a major health and economic
challenge in terms of healthcare costs, impaired quality of
life and lost working days. In Ireland, it is estimated that
diarrhoea is the main reason for approximately 40,000
visits to gastroenterology clinics annually.
However, despite the tremendous health and societal
burdens that they pose, therapeutic options for diarrhoeal
diseases are still limited. Research carried out at the Royal
College of Surgeons in Ireland in collaboration with Trinity
College Dublin and John's Hopkins University, Baltimore,
USA, has uncovered a new route for the development of
anti-diarrhoeal drugs which directly targets the cells and
molecular processes that control water movement into
the intestine.
The research shows that drugs which act on a protein
called Farnesoid X Receptor (FXR) in the intestine can
stop water moving into the gut and therefore prevent
diarrhoea from occurring. Since drugs which act on the
FXR protein directly target the cells responsible for water
movement into the gut, they may have broader efficacy
and fewer side effects than many currently available anti-
diarrhoeals. These findings support a patent for treating
diarrhoeal diseases recently granted to RCSI by the
European Patent Office and which is currently pending at
the US Patent Office.
The paper: Farnesoid X Receptor Agonists Attenuate
Colonic Epithelial Secretory Function and Prevent
Experimental Diarrhoea in vivo, Gut 63: 808-17, 2014. The
authors: Mroz MS, Keating N, Ward JB, Sarker R, Amu S,
Donowitz M, Fallon PG, Keely SJ.