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Wellcome Centre for Mitochondrial Research Institute of Translational and Clinical Research Faculty of Medical Sciences

Wellcome Centre for Mitochondrial Research

The Wellcome Centre for Mitochondrial Research, Newcastle University was established in 2012 and is built on a long-standing clinical and scientific expertise in mitochondrial disease and mitochondrial biology. Bringing together ~80 researchers and clinicians, its mission is to transform the lives of patients with mitochondrial disease through three key aims:

1. Understand the clinical course of patients with mitochondrial disease and how this relates to underlying disease mechanisms
2. Delineate molecular and genetic mechanisms causing mitochondrial disease
3. Develop techniques to prevent transmission of mitochondrial DNA disease and improve treatment for patients with mitochondrial disease and dysfunction.

Aligned with the academic team, the nationally commissioned NHS Highly Specialised Service for Rare Mitochondrial Disorders within Newcastle upon Tyne Hospitals NHS Foundation Trust provides an integrated multidisciplinary service for the diagnosis and clinical management of patients with mitochondrial disease (). Professor McFarland is national director of the service which is run in conjunction with teams at 911爆料网H and Oxford. The Newcastle service combines multidisciplinary clinical provision and laboratory testing, focussing on a 鈥榞enetics first鈥� approach to diagnosis supported by a suite of accredited functional (biochemical, histochemical, immunohistochemical) analyses and is part of the North East and Yorkshire Genomic Laboratory Hub, of which Professor Taylor is the Scientific Director. A comprehensive clinical care pathway and specific mitochondrial laboratory expertise underpin Newcastle as the only centre in the UK licensed to provide pre-implantation genetic diagnosis and mitochondrial donation as reproductive options for women with mitochondrial DNA related disease.

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Co-Investigator and Fellows Supervision Lead: Professor Robert McFarland

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ICGNMD research/role description: Alongside Professors Taylor and Straub, I am one of three PIs within the Newcastle team, providing support to the genomic projects undertaken by affiliated clinical fellows on the international fellowship training programme as well as the locally-affiliated clinical fellow and centre bioinformatician. I am ICGNMD Newcastle lead for clinical fellows and education and training.听I have extensive experience of clinical cohort development (MitoCohort UK) and through ICGNMD have developed collaborative links with colleagues in South Africa.

Relevant interests/other roles: I am Professor of Paediatric Mitochondrial Medicine and a consultant paediatric neurologist. My research interests in mitochondrial disease include both translational (gene discovery and function; neuropathological studies) and clinical (natural history; disease modelling and IMP clinical trials). I am also Director of the NHS Highly Specialised Service for Rare Mitochondrial Disorders, a nationally commissioned service provided through centres in Newcastle, London and Oxford.

Co-investigator: Professor Robert Taylor

ICGNMD role: Alongside Professors McFarland and Straub, I am one of three PI鈥檚 within the Newcastle team, providing support to the genomic projects undertaken by affiliated Clinical Fellows on the international fellowship training programme as well as the locally-affiliated Clinical Fellow and Centre Bioinformatician. Relevant to the mitochondrial projects, my laboratory has led on the writing the ACMG Best Practice guidelines for mitochondrial disease (updated 2021) and guidance for the laboratory interpretation of mitochondrial DNA variants.

Relevant interests/ other roles: I am Professor of Mitochondrial Pathology at Newcastle University, leading a research laboratory focused on mitochondrial gene discovery and disease mechanisms within the Wellcome Centre for Mitochondrial Research. I also lead the Highly Specialised Mitochondrial laboratory team in Newcastle, and undertake regional and national leadership roles in NHS Genomics as Scientific Director of the North East and Yorkshire Genomic Laboratory Hub and co-chair of NHS England鈥檚 Genomics Test Evaluation Working Group for Rare & Inherited Disease.

ICGNMD Clinical PhD Fellow:

Dr Mahmoud Fassad

Key Staff:

Dr Krutik Patel

Current research programmes:

The WCMR has three core pillars of research: clinical research, precision medicine and discovery therapeutics. In addition to clinical trial collaborations with the pharmaceutical industry, where we lead on clinical trial design, recruitment and delivery, our clinical research focuses on quantitative and qualitative growth of our longitudinal MitoCohort to improve both scientific understanding and raise international standards of care for mitochondrial disease. Our precision medicine research complements clinical and basic research themes, leveraging available big datasets to enhance a broad understanding of mitochondrial 鈥渙mics鈥� science in concert with a programme of work designed to understand the genetic architecture of mitochondrial disease and related mechanisms. In discovery therapeutics, we have developed high throughput phenotypic assays to screen chemical libraries with the purpose of identifying new small molecules that help restore mitochondrial function.

How the new international centre will benefit research and clinical programmes: 听

The ICGNMD will strengthen transcontinental genomics research and capacity building partnership between our Centre, other centres in the UK (UCL and Cambridge) and a number of other countries across the world including India, Brazil, South Africa, Zambia and Turkey. It will help with the discovery of new disease genes, defining the genetic variants in known neuromuscular genes, understanding comparative genetic architecture in different populations and exploring disease mechanisms. It will also strengthen transcontinental clinical academic partnerships in the field of neuromuscular diseases with the aim of improving the lives and health outcomes of children and adults affected by these diseases.

Recent publications:

1. Ol谩hov谩, M., Peter, B., Diaz-Maldonado, H., Szilagyi, Z., Singh, M., Sommerville, E.W., Blakely, E.L., Collier, J.J., Str谩neck媒, V., Hartmannov谩, H., Bleyer, A.J., McBride, K.L., Bowden, S.A., Korandov谩, Z., Pecinov谩, A., Ropers, H.H., Kahrizi, K., Najmabadi, H., Tarnopolsky, M., Brady, L.I., Weaver, K.N., Prada, C.E., 脮unap, K., Wojcik, M.H., Pajusalu S., Syeda, S.B., Pais, L., Estrella, E.A., Bruels, C.C., Kunkel, L.M., Kang, P.B., Bonnen, P.E., Mr谩膷ek, T., Kmoch, S., Gorman, G.S., Falkenberg, M., Gustafsson, C. and Taylor, R.W. (2021) POLRMT mutations impair mitochondrial transcription causing neurological disease. Nature Commun. 2021;12:1135 doi: 10.1038/s41467-021-21279-0.

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2. Alahmad, A., Nasca, A., Heidler, J., Thompson, K., Ol谩hov谩, M., Legati, A., Lamantea, E., Meisterknecht, J., Spagnolo, M., He, L., Alameer, S., Hakami, F., Almehdar, A., Ardissone, A., Alston, C.L., McFarland, R., Wittig, I., Ghezzi, D. and Taylor, R.W. Biallelic听 pathogenic variants in NDUFC2 cause early-onset Leigh syndrome and stalled biogenesis of Complex I. EMBO Mol. Med. 2020;12:e12619. doi: 10.15252/emmm.202012619.

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3. Alston, C.L.*, Veling, M.T.*, Heidler, J., Taylor, L.S., Alaimo, J.T., Sung, A.Y., He, L.,

听听听听听 Hopton, S., Broomfield, A., Pavaine, J., Diaz, J., Leon, E., Wolf, P., McFarland, R., Prokisch

听听听听听 H., Wortmann, S., Bonnen, P.E., Wittig, I., Pagliarini, D.J. and Taylor, R.W. Pathogenic

听听听听听 biallelic mutations in NDUFAF8 cause Leigh syndrome with an isolated complex I deficiency.

Am. J. Hum. Genet. 2020;106, 92-101. doi: 10.1016/j.ajhg.2019.12.001.

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4. Pickett, S.J., Blain, A., Ng, Y.S., Wilson, I.C., Taylor, R.W., McFarland, R., Turnbull, D.M.

and Gorman, G.S. Mitochondrial Donation - which women could benefit? New Engl. J. Med.

2019;380:1971-1972. doi: 10.1056/NEJMc1808565.

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5. Ng, Y.S, Martikainen, M.H., Gorman, G.S., Bugiardini, E., Jack, A., Schaefer, A.M.,

Alston, C.L., Blakely, E.L., Blain, A., Sharma, S., Hughes, I., Lim, A., DeGoede, C.,

McEntagart, M., Spinty, S., Horrocks, I., Roberts, M., Woodward C.E., Chinnery, P.F., Horvath, R., Nesbitt, V., Fratter, C., Poulton, J., Hanna, M.G., Pitceathly, R., Taylor, R.W., Turnbull, D.M. and McFarland, R. Pathogenic variants in MT-ATP6: A UK-based mitochondrial disease cohort study. Ann. Neurol. 2019;86:310-315. doi: 10.1002/ana.25525.

6. Thompson, K., Mai, N., Ol谩hov谩, M., Scialo, F., Formosa, L.E., Stroud, D.A., Garett, M., Lax, N.Z., Jou, C., Nascimento, A., Ortez, C., Jimenez-Mallabrera, C., Hardy, S.A., He, L., Brown, G.K., Marttinen, P., McFarland, R., Sanz, A., Battersby, B.J., Bonnen, P.E., Ryan, M.T., Chrzanowska-Lightowlers, Z.M.A., Lightowlers, R.N. and Taylor, R.W. Biallelic mutations in OXA1L cause a mitochondrial encephalopathy and combined oxidative phosphorylation dysfunction. EMBO Mol. Med. 2018;10:e9060. doi: 10.15252/emmm.201809060.

7. Grady, J.P.*, Pickett, S.J.*, Ng, Y.S., Alston, C.L., Blakely, E.L., Hardy, S.A., Feeney, C.L., Bright, A.A., Schaefer, A.M., Gorman, G.S., McNally, R., Taylor, R.W., Turnbull, D.M. and McFarland, R. (2018) Modelling disease burden and progression in m.3243A>G-related

mitochondrial disease: age-adjusted blood heteroplasmy levels are the most informative

measure of mutation load. EMBO Mol. Med. 2018;10:e8262. doi:10.15252/emmm.201708262.

8. Thompson, K., Majd, H., Dallabona, C., Reinson, K., King, M.S., Alston, C.L., He, L., Lodi, T., Jones, S., Fattal-Valevski, A., Fraenkel, N., Saada, A., Chaham, A., Isohanni, P., Vara, R., Barbosa, I.A., Simpson, M.A., Deshpande, C., Pussepp, S., Bonnen, P.E., Rodenburg, R.J., Suomalainen, A., Ounap, K., Elpeleg, O., Ferrero, I., McFarland, R., Kunji, E.R.S. and Taylor, R.W. (2016). Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number. Am. J. Hum. Genet. 2016;99:860-876. doi: 10.1016/j.ajhg.2016.08.014.

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