One gene closer to helping sufferers of rare genetic disorder

A new study has separately confirmed and significantly built on recent research, identifying mutations of a gene that causes the uncommon but potentially fatal Adams-Oliver syndrome.

A leading team of medical and genetics experts from institutions across Europe independently identified a gene called NOTCH1 while also discovering the largest range of mutations, both consolidating and expanding previous research published in 2014.

The new findings, published in the journal Circulation: Cardiovascular Genetics, solidify Notch signalling as a major factor in Adams-Oliver syndrome (AOS) and further advance diagnosis and treatment of this neonatal disorder – characterised by limb and scalp defects, accompanied by a host of cardiac and vascular complications.

The identification of the gene was driven by Professor Richard Trembath and Dr Laura Southgate, from Queen Mary University of London, with subsequent functional analyses primarily conducted by Dr Rajiv Machado and colleagues at the University of Lincoln, UK.

The study’s joint senior author Dr Machado, from the School of Life Sciences, University of Lincoln, said: “Our study, which provides the largest collection of NOTCH1 mutations to date, clearly places this gene as a major causal genetic factor in AOS and in particular when associated with major cardiovascular defects, both developmental and structural.

“This insight into NOTCH1 offers the potential to explain its function in the development of key systems in the body – notably cardiovascular, skeletal and pulmonary systems. The ultimate hope is further research in this area will result in more effective diagnoses, but most importantly treatment therapies, for those affected with this debilitating condition.”

The initial gene identification process was based on sequencing the genomes of 12 families affected with AOS. They found that two people from different families had mutations in the NOTCH1 gene. Confirmation of these findings was obtained by screening a cohort of 52 additional patients, which led to the identification of a further eight unique mutations.

This study, combined with the earlier publication of NOTCH1 mutations in AOS, is a significant breakthrough in the understanding of this developmental disorder, which currently has no cure.

In 2011, Dr Machado and Dr Southgate were integral to efforts that led to the discovery of the ARHGAP31 gene – the first identified molecular defect associated with AOS. This finding was noted by international publications including the American Journal of Medical Genetics which provided an editorial to mark the work.

Since then four additional genes, including NOTCH1, have been identified indicating this is a disease underpinned by multiple genetic factors.

The collaboration is currently further examining the impact of NOTCH1 mutations described in this study and exploring the possibility of additional mutations in as yet unidentified genes in an extensive cohort of patients.

This work was supported by the British Heart Foundation, the German Research Foundation and a Wellcome Trust Strategic Award.

Leading academic on cardiovascular disease joins University

A scientist who discovered the genes that cause a disease linked to lung and heart failure has joined the team at the University of Lincoln’s School of Life Sciences.

Dr Rajiv Machado was previously a recipient of an independent British Heart Foundation fellowship in the Division of Genetics and Molecular Medicine, King’s College London.

He discovered the major gene that causes Pulmonary Arterial Hypertension (PAH) while in the third year of his PhD at the University of Leicester’s Department of Medical Genetics in 2000.

The condition is a progressive disorder characterised by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Symptoms are shortness of breath, dizziness, swelling (oedema) of the ankles or legs, chest pain and a racing pulse.

Dr Machado said: “Pulmonary Arterial Hypertension is fairly uncommon but extremely important in terms of understanding the way in which the lung works. Research in this area informs a huge number of more common diseases. It is currently incurable and has a high mortality rate. In terms of diagnosis and treatment the research I am doing opens up a number of new pathways we need to go down.”

The discovery of the PAH gene established Dr Machado’s name in the field of genetics and led to a surge in publications, foremost of which was the report of this work in the prestigious journal Nature Genetics. The findings were also awarded an American patent.

Dr Machado’s continuing research has since been featured in many other journals including one of the highest impact factor ranking publications in the world, The New England Journal of Medicine in which he and colleagues reported the identification of a second gene predisposing to forms of pulmonary hypertension. More recently, he reported the contribution of three more genes within the same pathway as underlying this spectrum of disease.

In 2008 Dr Machado was co-chairman of the Genetics and Genomics Committee at the third World Health Organisation (WHO) conference on pulmonary hypertension, producing a seminal paper in the Journal of American College of Cardiology (JACC). Dr Machado is attending the WHO summit in February 2013, for which he has already written a paper that will be combined with inputs from other eminent health experts.

The summit will seek to incorporate ideas and lessons from regional and international consultations, thereby building a powerful consensus around key issues and recommendations on health to feed into the global process that will start later in 2013.

Dr Machado said: “It will set the ground rules to our state of knowledge. Following the summit a seminal statement will be issued on where we are going as understood by the WHO. It really does inform clinical practice, basic science and treatment.”

In 2011, Dr Machado was integral to efforts that led to the discovery of a gene underlying the developmental disorder Adams-Oliver syndrome, characterised by limb and scalp defects, accompanied by a host of cardiac and vascular complications. This finding was noted by international publications including the American Journal of Medical Genetics which provided an editorial to mark the work.

On his appointment at the University of Lincoln, Dr Machado said: “The reason Lincoln is so appealing is that it is a university full of ambition with really good people at the helm. The institution has got the wherewithal to build a new research park which is going to be world-class. With the team of academics now in place at the University this is a place that is definitely moving forward fast and it is exciting to be a part of that.”