Inherited manganese transporter defects

Manganese is an essential trace metal and critical for brain physiology and development. However, excess manganese is neurotoxic leading to dystonia-parkinsonism, psychiatric and intellectual disability.

Our research has identified two manganese transporter defects associated with manganese neurotoxicity – hypermanganesaemia with dystonia 1 (HMNDYT1) and 2 (HMNDYT2). They are caused by loss-of-function mutations in SLC30A10 and SLC39A14, respectively, that encode manganese transporters that act in conjunction to mediate metal excretion. Manganese deposition in the brain leads to progressive, childhood-onset dystonia-parkinsonism associated with significant disability and premature death.

Our lab uses manganese transporter mutant zebrafish as models for manganese overload/deficiency in order to dissect how metal dyshomeostasis disrupts neurons, synapses and circuit function with the view to identifying new therapeutic targets. In addition, we are working to develop novel therapeutic approaches to improve treatments for disorders associated with Mn neurotoxicity. 

VITAMIN B6 DEPENDENT EPILEPSY

Vitamin B6, normally present in our diet, is critical for brain function. Children with inherited disorders that lead to severe deficiency of B6 suffer from seizures, delayed neurodevelopment and brain malformations.

In collaboration with Prof Philippa Mills (UCL GOS ICH) and Dr Richard Rosch (Imaging Neuroscience) we are trying to better understand the consequences of B6 deficiency on brain function. Using zebrafish disease models that recapitulate the seizure disorders observed in affected children, we will investigate how imbalance of B6 impairs the chemical messengers ('neurotransmitters') in the brain that are required to transmit messages from a nerve cell to a target cell. Thereby, we hope to identify novel therapeutic targets that can be translated into new treatments for affected children to prevent disability and improve children’s quality of life.

Tuschl Lab News

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about me

Lab Members

Past Lab Members

Artur Fernandes – Postdoc

Rebecca Wills – MSc GHD student

Aanandita Kothurkar – MSc GHD student

Anabel Alba González - Visiting PhD Student

Valeria Nikolaenko- Postdoc

Collaborators

• Prof Stephen Wilson, Department of Cell and Developmental Biology, UCL

• Prof Ahad Rahim, School of Pharmacy, UCL

• Prof John Spencer & Dr George Kostakis, Department of Chemistry, University of Sussex

• Prof Philip Blower, Department of Imaging Chemistry and Biology, KCL

• Prof Philippa Mills, UCL GOS Institute of Child Health

• Dr Richard Rosch, Wellcome Trust Centre for Neuroimaging, UCL

• Dr Ryan Macdonald, Institute of Ophthalmology, UCL

• Prof Thomas Bartnikas, Brown University, US

• Prof Giulio Superti-Furga, Centre for Molecular Medicine, Vienna, Austria

• Dr Mónica Folgueira, Centro Interdisciplinar de Química y Biología, (CICA), University of A Coruña, Spain

Lab Photos

 Selected publications

Alba-González, A.; Dragomir, E.I.; Haghdousti, G.; Yáñez, J.; Dadswell, C.; González-Méndez, R.; Wilson, S.W.; Tuschl, K.; Folgueira, M. Manganese Overexposure Alters Neurogranin Expression and Causes Behavioral Deficits in Larval Zebrafish.
Int. J. Mol. Sci. 2024, 25, 4933. https://doi.org/10.3390/ijms25094933

Gurung S, Karamched S, Perocheau D, Seunarine KK, Baldwin T, Alrashidi H, Touramanidou L, Duff C, Elkhateeb N, Stepien KM, Sharma R, Morris A, Hartley T, Crowther L, Grunewald S, Cleary M, Mundy H, Chakrapani A, Batzios S, Davison J, Footitt E, Tuschl K, Lachmann R, Murphy E, Santra S, Uudelepp ML, Yeo M, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Frassetto A, Heales S, Mills PB, Gissen P, Clayden JD, Clark CA, Eaton S, Kalber TL, Baruteau J.
The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.
J Inherit Metab Dis. 2023. doi: 10.1002/jimd.12691.

Messina M, Manea E, Cullup T, Tuschl K, Batzios S.
Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid.
JIMD Rep. 2022 Nov 22;64(1):42-52.

Tuschl K, White RJ, Trivedi C, Valdivia LE, Niklaus S, Bianco IH, Dadswell C, González-Méndez R, Sealy IM, Neuhauss SCF, Houart C, Rihel J, Wilson SW, Busch-Nentwich EM.
Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
Dis Model Mech. 2022. doi: 10.1242/dmm.044594.

Tuschl K, Taylor CA, Nicolai MM, Bornhorst J, Gubert P, Varão AM, Aschner M, Smith DR, Mukhopadhyay S.
Maintaining Translational Relevance in Animal Models of Manganese Neurotoxicity.
J Nutr. 2020;150:1360-1369.

Tuschl K, White RJ, Valdivia LE, Niklaus S, Bianco IH, Sealy IM, Neuhauss SCF, Houart C, Wilson SW, Busch-Nentwich EM.
Loss of slc39a14 causes simultaneous manganese deficiency and hypersensitivity in zebrafish.
doi.org/10.1101/2020.01.31.921130 

Tuschl K, Yapici Z, Eraksoy M.
Hypermanganesemia with dystonia 1 – a novel mutation and response to iron supplementation.
Mov Disord Clin Pract. 2019. 7:94-96.

Anagianni S, Tuschl K.
Genetic Disorders of Manganese Metabolism.
Curr Neurol Neurosci Rep. 2019. 19:33.

Baguña Torres J, Yu Z, Bordoloi J, Sunassee K, Smith D, Smith C, Chen O, Purchase R, Tuschl K, Spencer J, Platt F, Blower PJ.
Imaging of changes in copper trafficking and redistribution in a mouse model of Niemann-Pick C disease using positron emission tomography.
Biometals. 2019. 32:293-306.

Rodan LH, Hauptman M, D'Gama AM, Qualls AE, Cao S, Tuschl K, et al.
Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies.
Mol Genet Metab. 2018. 124:161-167.

Tuschl K, Gregory A, Meyer E, Clayton PT, Hayflick SJ, Mills PB, Kurian MA.
SLC39A14 Deficiency.
In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors.
GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2018.

Tuschl K, Meyer E, Valdivia LE, Zhao N, Dadswell C, Abdul-Sada A, Hung CY, Simpson MA, Chong WK, Jacques TS, Woltjer RL, Eaton S, Gregory A, Sanford L, Kara E, Houlden H, Cuno SM, Prokisch H, Valletta L, Tiranti V, Younis R, Maher ER, Spencer J, Straatman-Iwanowska A, Gissen P, Selim LA, Pintos-Morell G, Coroleu-Lletget W, Mohammad SS, Yoganathan S, Dale RC, Thomas M, Rihel J, Bodamer OA, Enns CA, Hayflick SJ, Clayton PT, Mills PB, Kurian MA, Wilson SW.
Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.
Nat Comms. 2016. 7:11601

Tuschl K, Mills PB, Clayton PT.
Manganese and the brain.
Int Rev Neurobiol. 2013. 110:277-312

Tuschl K, Clayton PT, Gospe SM, Mills PB.
Dystonia/Parkinsonism, Hypermanganesemia, Polycythemia, and Chronic Liver Disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors.
GeneReviews™. Seattle (WA): University of Washington, Seattle; 2012 (updated 2014)

Tuschl K, Stamelou M, Chong WK, Burroughs AK et al.
Dystonia with brain manganese accumulation resulting from SLC30A10 mutations: a new treatable disorder.
Mov Disord. 2012. 27:1317-1322

Tuschl K, Clayton PT, Gospe SM, Shamshad G, et al.
Syndrome of hepatic cirrhosis, dystonia, polycythaemia and hypermanganesaemia – caused by mutations in SLC30A10, a manganese transporter in man.
Am J Hum Genet. 2012. 90:457-466

Our research is generously funded by:

Contact

For all inquiries please email: k.tuschl@ucl.ac.uk

UCL Great Ormond Street Institute of Child Health
30 Guilford Street
London WC1N 1EH

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GOS ICH
Genetics and Genomic Medicine at GOS ICH