MDUK LGMD Muscles Matter Seminar Series

Muscular Dystrophy UK, a charity that has funded our group, deliver online seminars on a range of topics and to mark condition awareness days, weeks and months. The seminars are targeted at patients, families, friends and anyone generally interested in the topics covered. On the 30th September, it is Limb Girdle Muscular Dystrophy (LGMD) Awareness Day, and our group was invited back to take part in the MDUK seminar. Last year we focused our talk on one of our projects which aimed to investigate a small cohort of undiagnosed LGMD families and which had just received funding from MDUK. This year it was great to be able to share some of our results as well.

The seminar included talks from clinical and healthcare specialists, along with a patient representative. It was really valuable hearing from the audience - many of whom are patients themselves, as to what issues are important to them.

The seminars can be watched again on the MDUK Youtube channel here: MDUK Muscles Matter 2021: Limb girdle muscular dystrophy (LGMD)

MRC funded PhD studentship available - Tackling Rare Neuromuscular Diseases

Apply for an MRC DTP fully-funded PhD.

The project “Tackling rare neuromuscular diseases” will make use of whole exome, genome and SNP data from a large cohort of patients with neuromuscular disease to learn more about the molecular cause in undiagnosed patients, and provide further knowledge of the underlying functional mechanisms using the zebrafish as a model organism.

The deadline for applications is Wednesday 1 January 2020. We can only accept applications from those with UK/EU nationality.

Please note there is a Proposal Writing component to the application, and therefore it is recommended that you contact the supervisors as soon as possible for advice before submitting.

project summary

Limb-girdle muscular dystrophies (LGMD's) comprise 30% of all progressive muscular dystrophies, collectively affecting up to 500,000 individuals worldwide. Unfortunately, no definitive treatments for LGMD exist.

A significant obstacle in the development of treatments for LGMD is the lack of a genetic diagnosis in up to 50% of patients, coupled with incomplete knowledge of the underlying disease mechanisms. However, we and others have demonstrated that recent advances in gene sequencing can successfully be used to identify novel neuromuscular disease genes, and that model organisms can be used to validate the role of these genes in muscle development and disease.

This project will use state of the art genetic techniques to identify the molecular cause in undiagnosed LGMD patients and provide further knowledge of the underlying mechanisms using the zebrafish as a model organism.

The project will equip the student with a range of versatile skills including analysis of genetic data, bioinformatics, and in vivo disease modelling.

Applicants must have obtained, or be about to obtain, an MSc/MRes or BSc (2i or above) in biology, molecular biology, genetics, statistical genetics, bioinformatics, or a related field in a science discipline. Prior experience in basic laboratory skills is essential. Applicants should have an interest in bioinformatics, be able to communicate data and ideas effectively, and be willing to travel internationally to attend meetings with collaborators.

Who we are and what we are looking for:

We believe in a multi-disciplinary approach to science where each team member plays an important role in moving towards our goal of identifying the genetic cause of rare diseases and ultimately understanding the underlying mechanisms.

We are looking for individuals who are creative and independent thinkers with a passion for research, who have plenty of self-motivation, and the ability to work well within a team.

Reading lots of papers within your field and more widely is an important skill which will also allow you to be more creative in your thinking. Your PhD is not only about getting your research project and thesis done, but also an important training period, our Institute has an allocated travel budget for conferences, and the MRC LID program also includes funds towards workshops and training.

The high collegiality among the lab members can be seen in our list of publications where you will find undergraduate students, graduate students, postdocs and PI as authors.

Our labs sit within a larger shared space where you will find helpful postdocs from other groups with expertise in different techniques. They are always willing to help and give valuable advice.

Maintaining a healthy work–life balance by finding a routine that works for you is important. We’re not a 9 to 5 lab - if you’re being productive then we’re happy. However, everyone is expected to participate in lab meetings and departmental seminars.

If you’re thinking of applying or have any questions please get in touch :-) yjamshid@sgul.ac.uk

why Study at St George’s

St George’s, University of London is the United Kingdom’s only university dedicated to medical and health sciences education, training and research. We are based in Tooting, south west London, and share a site with St George's Hospital. St. George’s Hospital Medical School was established in 1733 and alumni include pioneers in medicine, John Hunter (founder of modern surgery), Edward Jenner (founder of smallpox vaccine), Henry Gray (wrote Grays anatomy) and Patrick Steptoe (pioneered fertility treatment and IVF). It is currently home to over 5,500 students and over 800 members of staff.

Our Genetics Research Centre is part of a larger Molecular and Clinical Sciences Institute within St George’s. Our research is highly collaborative between the University and St George’s Hospital Trust and further afield nationally and internationally.

We have excellent infrastructure and facilities at St George’s which include a core Image Resource Facility (IRF), a Nikon Centre of Excellence, providing access for researchers to bioimaging techniques that include Transmission Electron Microscopy (TEM), Confocal and Light Sheet Microscopy, and sample embedding and Histological techniques.

New gene for Hereditary Spastic Paraplegia

In collaboration with researchers from Germany, the USA, Tunisia and Iran we recently reported a new gene for hereditary spastic paraplegia (HSP).

The study, published in Nature Communications, also highlights a potential mechanism for the disease, which is already being targeted in drug trials for Alzheimer’s and Huntington’s diseases.

HSP is an inherited condition that causes stiffness and weakness in the leg muscles, often leading to patients becoming wheelchair-bound. Gradually getting worse over time, and with no treatments currently available, patients can only be offered muscle relaxants, which help the muscles to cope with the inability to move smoothly. Some patients with more complex forms of HSP can also have problems with their eyes, and intellectual impairment.

Several genes have already been linked with HSP, which causes degeneration of the nerves that lead down from the brain. But these genes only account for around two-thirds of patients with the condition. The new gene RNF170 identified gives doctors the opportunity to test for the disease in the other third of patients with no clear genetic diagnosis.

Our study also went on to try and understand the mechanism by which the gene mutations cause HSP using a zebrafish model and studies in cells. The results highlighted defects in the calcium signalling pathway essential for cell function. This pathway is already known to play a role in other diseases, such as Alzheimer’s and Huntington’s and so we hope that drugs being developed to tackle these diseases could also be used to improve treatments for HSP.

IAmSciComm Twitter Take Over

I recently did another Twitter take over - this time for the @!AmSciComm account. This is a rotating Twitter account for SciCommers run by Crastina and colleagues from SciComm Hub. “SciComm Hub is a community and collection of resources focused on science education, outreach, and communication. The Hub aims to assist students in exploring and finding careers in science communication, to provide a space for students, postdocs, and faculty to interact and network in the context of science communication, and to connect students to relevant resources and opportunities.”

The account has over 20K followers and during my week we discussed everything from putting together your “Elevator Pitch” to the #ethics of science communication. In fact you’ll find a summary of the “Elevator Pitch” discussion in the resources page.

It was a great opportunity to connect with an audience of interested SciCommers, and I highly recommend signing up to do a take over. You can add your details if you want to be considered - here…. and if you’re not following the @!AmSciComm account already, I highly recommend you do!

Rare Disease Day 28th February

To mark Rare Disease Day (28th February) our genetics research centre organised an event in the university/hospital foyer to raise awareness of the difficulties #raredisease families face and to share some of the work we do.

Rare diseases are defined as those affecting fewer than 1 in 2000 individuals, but whilst a single rare disease may affect only a handful of patients, collectively as many as 30 million people in the EU alone could be affected. Importantly for many of these diseases, 80% of which have genetic origins, there is very little knowledge of the underlying causes and even fewer effective treatments. Members of our research centre work on a variety of rare diseases, trying to improve diagnosis by identifying #genes causing them, and developing therapies based on this information.

This was the first time we organised an event for Rare Disease Day, and so we were unsure of how well it would be received and whether or not we would get anyone stopping by. But we needn’t have worried as we had almost 200 people pass through on the day. We also had a great response on social media where we were posting short bios of our research centre members and their work throughout the day. 

 We were able to reach out to the general public and explain rare diseases to them, as well as students and staff from across the hospital and medical school. Many people were unaware of the research we undertake in the Genetics Centre and it was a pleasure to be able to share some of our latest discoveries and vital work. It was also a great way to interact with people and understand the public perception on rare diseases. Most people were really surprised to hear that although rare diseases are individually rare, collectively they are quite common. 

We all enjoyed taking part in the day, We’re looking forward to making next years event even bigger and better.

New gene for cardiomyopathy identified

Photo by James Graham on Unsplash

Cardiomyopathy is the leading cause of sudden death in young people, and an important cause of heart failure at any age. Hypertrophic cardiomyopathy (HCM) is typically associated with autosomal dominant mutations in genes encoding proteins of the sarcomere. Dilated cardiomyopathy (DCM), also results from mutations in some of the same sarcomeric proteins but leads to ventricular chamber dilation and reduced systolic performance, rather than hypertrophy.

Despite technological advances in genetic testing, a definitive molecular diagnosis is obtained for only 50% of patients. We therefore need to understand more about the genetic determinants underpinning cardiomyopathy, which will expand our knowledge of the underlying disease mechanisms and lead to possible new therapeutic approaches.

In our paper out this month we show using genome-wide linkage analysis and exome sequencing that homozygous mutations in KLHL24 cause HCM in two consanguineous families. Of the eleven young affected adults in our study, three died suddenly and one had a cardiac transplant due to heart failure, highlighting the severity of this form of HCM. We also show that knock-down of the gene in zebrafish results in heart defects providing additional support for KLHL24 as a HCM-associated gene.

Cardiomyopathy with lethal arrhythmias associated with inactivation of KLHL24.

Hedberg-Oldfors C, Abramsson A, Osborn DPS, Danielsson O, Fazlinezhad A, Nilipour Y, Hübbert L, Nennesmo I, Visuttijai K, Bharj J, Petropoulou E, Shoreim A, Vona B, Ahangari N, López MD, Doosti M, Banote RK, Maroofian R, Edling M, Taherpour M, Zetterberg Md H, Karimiani EG, Oldfors A, Jamshidi Y.

Hum Mol Genet. 2019 Feb 1.

MinoritySTEM Twitter Take Over

So last week I did a Twitter take over for the Minorities in STEM account (@MinoritySTEM).

As described on the Minorities in STEM website although Black and Minority Ethnicity (BME) individuals make up 12.8% of the UK population, this is still not reflected within the public’s perception of what a scientist looks like. The aim of Minorities in STEM is to create a network that can connect, support and showcase the individuals working and studying within STEM.

During my take over some of the issues that were discussed included self-confidence and how important it is to first and foremost believe in yourself and your potential in a STEM role. It was also the perfect week as we had a Q&A session with the amazing Angela Saini (author of must read “INFERIOR”) at our university. Her new book available later this year will be another one to look out for as it takes on racism and the “science” behind it.

I found the Twitter community of followers really supportive and I would recommend following them on Twitter for lots of great opportunities and timely discussions.

They’re always on the look out for anyone who would be interested in contributing a few hours a month to the Minorities in STEM project as they grow so do get in touch through their website.

Gene-edited babies in the news

So you may know that one of the topics I’m interested in is Gene editing and its potential for treating rare disease. Well this weeks big news story across the world was about a Chinese researcher and his team who decided to move beyond the testing of gene editing in controlled clinical trials straight into human embryos. Even stranger rather than attempting to treat a patient with a rare disease he chose to modify healthy embryos to make them resistant to HIV.

As you can imagine the scientific world reacted with shock and disbelief. I also felt the need to put my opinion out there with the following comment on the story that was emerging….“Gene editing tools are fantastic for research but we are still not able to control them well enough to ensure they are safe and efficient for use in humans. The scientists who carried out these studies chose to focus on a gene associated with risk of HIV, however we already have ways to prevent HIV infection and available treatments should it occur. We also do not need gene editing to ensure it isn’t passed on to offspring. We know very little about the long term effects, and most people would agree that experimentation on humans for an avoidable condition just to improve our knowledge is morally and ethically unacceptable. Whether the results stand up to scrutiny or not we need as a society to think hard and fast about when and where we are willing to take the risks that come with any new therapeutic treatment, particularly ones that could affect future generations.”

Interestingly the story itself reached beyond the scientific community into the general public - a group that should rightly be interested in gene editing, its potentials and currently pitfalls/safety concerns. I agreed to speak to a couple of radio shows - firstly Patrick Chrystys lunch time show on LoveSport Radio, and then later Sputnik International. You can hear both my interviews on the Outreach Page of the website.

MRC funded PhD studentship available

Apply for an MRCDTP fully-funded PhD joint collaboration between our group & Dr Hilary Martin (Martin group).

The project “Characterising the genetic architecture of inherited cardiac conditions” will make use of data from the 100,000 Genomes Project, UK Biobank, and other disease cohorts to identify new genes underlying inherited cardiac conditions, and provide greater understanding of the role of common and rare variants, in coding and non-coding regions of the genome, in conditions classically thought of as monogenic.

The deadline for applications is Sunday 13th January 2019, click to find out more info and how to apply.

STEMinist Twitter Take Over

This week I had the opportunity to take over thte STEMinist Twitter Account. With over 20,000 followers it was amazing to connect with so many people working in STEM subjects - especially all the women in stem careers.

The STEMinist was created in 2010 by Ann Hoang, with a number of aims:

• Increase the visibility of women in STEM

• Promote and elevate the perspective of women in these traditionally underrepresented fields

• Encourage younger women and girls to pursue careers in STEM

• Capture a social media snapshot of what’s trending for women in STEM

You can link to the STEMinist website here and there Twitter page.

We had lots of interesting conversations, covering some important topics relevant to career progression and visibility. So much so that I’ve put some of the most useful info and links into the ECR Resources page on my site.

Hope you find it useful :-)

Back from ASHG, San Diego

The American Society of Human Genetics conference each year is a fantastic place to hear about the latest genetics research, meet old friends and colleagues, and make some new ones! This year was no different and to top it off it was in one of my favourite places - San Diego, California :-)

My presentation was part of the Gene Discovery and Functional Models of Neurological Disorders session on the first full day of the conference, and described some exciting new results as part of an ongoing collaboration to identify new genes for Hereditary Spastic Paraplegia.

It was a little scary thinking about getting up and speaking in a room full of experts but it was a great opportunity to share our work, and it felt great to be invited.

Of course I also made the most of my trip to San Diego with a few visits to some old haunts - and they didn’t disappoint!

All in all it was a great meeting and a fun trip to California!

in2science STEM Careers Speed Networking Event

On the evening of the 30th August in2science held a STEM Careers Speed Networking Event which Yalda took part in.

in2science is an award-winning organisation, giving students the opportunity to work alongside STEM scientists & progress to top universities and STEM careers.

It was a fantastic opportunity for Yalda to meet with students who had carried out summer project placements, and answer any questions they had about a future science-related career. There were experts from National Geographic, Science publishers such as Nature Communications, science communication experts, and many more for the students to talk to.

Biohacking BBC Radio 4 series

Biohacking

BBC Radio 4 recently presented a series on Biohacking which very nicely covered CRISPR, its use, problems, ethics and future directions. You can hear Yalda in the fourth episode in the series (available on BBC iPlayer - click the image below), talking about mosaicism. The show is presented by Jonathan Ball and produced by Alex Mansfield.

ASHG platform talk: New gene for hereditary spastic paraplegia

Excited to share the results from our recent collaborative work on a new gene for hereditary spastic paraplegia. Our abstract has been accepted for a platform presentation at this years American Society of Human Genetics meeting in San Diego.

So if you'd like to hear more come along to the Gene Discovery and Functional Models of Neurological Disorders session on Wednesday, October 17; Session Time: 4:15 pm - 5:45 pm :-)

Authors:
Y. Jamshidi1, M. Wagner2,9, I. Gehweiler3, S. Bakhtiari4,5, E. Ozkan1, R. Maroofian1, R. Boostani6, E. Ghayoor Karimiani7, S. Padilla-Lopez4,5, K. Vill10, H. Darvish8, D.P.S. Osborn1, M.C. Kruer4,5, J. Winkelmann2,9, R. Schüle3
Institutions:
1) St George's University of London, London, United Kingdom; 2) Institut für Humangenetik, Munich, Germany; 3) Center for Neurology and Hertie Institute for Clinical Brain Research, Tübingen, Germany; 4) Cerebral Palsy & Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Arizona, USA Children’s Hospital, Arizona, USA; 5) Departments of Child Health, Neurology, and Cellular & Molecular Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA; 6) Department of Neurology, Mashhad, Iran; 7) Next Generation Genetic Clinic, Mashhad, Iran; 8) Department of Medical Genetics, Semnan University of Medical Sciences, Semnan, Iran; 9) Institute for Neurogenomics, Helmholtz-Zentrum Munich, Munich; 10) Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Center for Neuromuscular Disorders in Childhood. Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Germany

Latest paper: New genes associated with heart rhythm

Excited to say our latest study on genes associated with heart rhythm is out today in the journal Genome Biology and you can download the full text by clicking here.

The paper describes the results from a large international collaboration which we led to identify new genes associated with heart rhythm and function.

An electrocardiogram (or ECG), which records a heart's rhythm and electrical activity, can be used to identify life-threatening heart problems which often have a strong genetic basis. The team compared ECGs and the genetic makeup of almost 200,000 individuals to gain insight into the genetics that underlie heart rhythm. This was done using large-scale genetic association studies focusing on protein-coding parts of the genome.  We chose to focus on rare variants that are often missed in large scale population studies, for follow-up.

The results, published in Genome Biology, confirmed previously-known associations between genetic regions and the heart’s electrical signature, but also highlighted a role for rare gene variants found in less than 1% of the population.

Our team focused on one particular protein, ADAMTS6, to investigate further. Very little is currently known about its function. In a series of experiments in cells, to characterize the consequences of carrying a rare genetic variant in ADAMTS6, we found that the protein is not secreted as well as a fully functional copy of the gene.

Furthermore, using mouse models, we show that carrying only one copy of a poorly functioning gene results in a decrease in Connexin 43, the molecule that transmits the electrical signal between adjacent heart cells and is essential for the cells to communicate. This decrease could be responsible for the subtle changes in heart rhythm seen in the initial population study.

However, when both copies were not functional, it resulted in complete absence of Connexin 43 and serious problems in heart development.

These findings increase our knowledge of the genes involved in regulation of heart rhythm, and suggest that whilst carrying a single rare damaging variant in ADAMTS6 may result in only subtle changes in electrical activity of the heart, carrying two copies could be a cause of congenital heart defects which affect up to 8 in every 1,000 babies born in the UK.

Greater knowledge of the genes determining normal heart rhythm will support efforts to develop new drugs to treat abnormal heart rhythms, but first further work will be needed to fully characterise the function of all the genes identified in our study.

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, which funded the study, said:
“Right now, we estimate that there are around 620,000 people in the UK carrying any one of dozens of faulty genes that could kill them - genes that puts them at higher risk of premature coronary heart disease or sudden cardiac arrest.

“BHF-funded research has led to identification of many of these genes but there is still an urgent need for better diagnosis of genetic heart conditions so that people get the advice or treatment they need to prevent a tragedy.  The results from the current study are another step towards achieving that goal.”    

The work was funded by a British Heart Foundation Project Grant (PG/12/38/29615)

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Prins et al. Genome Biology  (2018) 19:87 https://doi.org/10.1186/s13059-018-1457-6

Sharing a little of what we do with........Eva

This week we're hosting Eva who is a student at Surbiton High School. She's just finished her GCSE's and will be taking A-levels in Biology, Chemistry and Maths. Having spent a couple of days in the hospital with the echo team and blood lab she's now getting a chance to see what we get up to in the Genetics labs :-)

Welcome to our summer placement student Ivana

The summer placements are well underway, and we're lucky enough to be joined by Ivana who will be entering the final year of Genetics this September at Trinity College Dublin. She will be working with us over the summer analysing exome sequencing data to help identify the disease causing genes and mutations in some of our rare disease families.

Ivana also joined us last week at the Genomic Health meeting in Charterhouse Square as you can see below ;-) It was a fantastic opportunity to hear some excellent speakers discuss their work and of course to chat with them over nibbles afterwards.

International Womens Day

Yesterday was a lovely opportunity to meet some young women attending the Arts and Media School in Islington as part of an event to inspire women to take up STEM subjects. The event was organised by Will Hoyles and sponsored by Accenture. The afternoon involved an initial networking lunch where the students could ask questions in small groups, and then followed with a presentation of awards to a number of the students. Finally, the afternoon ended with a screening of the movie Hidden Figures, which is based on the non-fiction book of the same name by Margot Lee Shetterly. The story is about three black female mathematicians who worked at the National Aeronautics and Space Administration (NASA) during the Space Race. I hadn't seen it before and really enjoyed it - a movie I would definitely recommend watching!

So thanks to everyone I met and the organisers for a fantastic afternoon!