Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia PMID: 27231142

ADC Targets in Oncology

2026-04-10

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia

Nat Commun. 2016 May 27;7:11601. doi: 10.1038/ncomms11601.

Karin Tuschl ¹ ² , Esther Meyer ³ , Leonardo E Valdivia ² , Ningning Zhao ⁴ , Chris Dadswell ⁵ , Alaa Abdul-Sada ⁵ , Christina Y Hung ⁶ , Michael A Simpson ⁷ , W K Chong ⁸ , Thomas S Jacques ⁹ , Randy L Woltjer ¹⁰ , Simon Eaton ¹¹ , Allison Gregory ¹² , Lynn Sanford ¹² , Eleanna Kara ¹³ ¹⁴ , Henry Houlden ¹³ , Stephan M Cuno ¹⁵ ¹⁶ , Holger Prokisch ¹⁵ ¹⁶ , Lorella Valletta ¹⁷ , Valeria Tiranti ¹⁷ , Rasha Younis ¹⁸ , Eamonn R Maher ¹⁹ ²⁰ , John Spencer ⁵ , Ania Straatman-Iwanowska ²¹ , Paul Gissen ¹ ²¹ ²² , Laila A M Selim ²³ , Guillem Pintos-Morell ²⁴ , Wifredo Coroleu-Lletget ²⁵ , Shekeeb S Mohammad ²⁶ , Sangeetha Yoganathan ²⁷ , Russell C Dale ²⁶ , Maya Thomas ²⁷ , Jason Rihel ² , Olaf A Bodamer ⁶ , Caroline A Enns ⁴ , Susan J Hayflick ¹² ²⁸ ²⁹ , Peter T Clayton ¹ , Philippa B Mills ¹ , Manju A Kurian ³ , Stephen W Wilson ²

Affiliations

1. Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
2. Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
3. Developmental Neurosciences, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
4. Department of Cell, Development and Cancer Biology, Oregon Health &Sciences University, Portland, Oregon 97239, USA.
5. Department of Chemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
6. Division of Genetics and Genomics, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
7. Division of Genetics and Molecular Medicine, King's College London School of Medicine, London SE1 9RT, UK.
8. Department of Radiology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
9. Developmental Biology and Cancer, UCL Institute of Child Health and Department of Histopathology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
10. Department of Pathology, Oregon Health &Science University, Portland, Oregon 97239, USA.
11. Developmental Biology and Cancer Programme, UCL Institute of Child Health, University College London, London WC1N 1EH, UK.
12. Department of Molecular &Medical Genetics, Oregon Health &Science University, Portland, Oregon 97239, USA.
13. Institute of Neurology, University College London, London WC1N 3BG, UK.
14. Alzheimer's Disease Research Centre, Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
15. Institute of Human Genetics, Technische Universität München, Munich 81675, Germany.
16. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg 85764, Germany.
17. Unit of Molecular Neurogenetics, IRCCS, Foundation Neurological Institute 'C. Besta', Milan 20133, Italy.
18. Department of Medical and Molecular Genetics, University of Birmingham, Birmingham B15 2TT, UK.
19. Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
20. Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Cambridge CB2 0QQ, UK.
21. MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, University College London, London WC1E 6BT, UK.
22. Department of Metabolic Medicine, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
23. Department of Paediatric Neurology, Faculty of Medicine, Cairo University Children's Hospital, Cairo 11432, Egypt.
24. Department of Paediatrics, Section of Paediatric Nephrology, Genetics and Metabolism, Unit of Rare Diseases, University Hospital 'Germans Trias I Pujol', Universitat Autònoma de Barcelona, Badalona 08916, Spain.
25. Department of Paediatrics, Paediatric Neurology and Neonatology Unit, University Hospital 'Germans Trias I Pujol', Badalona 08916, Spain.
26. Neuroimmunology Group, Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children's Hospital at Westmead, University of Sydney, Westmead NSW 2145, Australia.
27. Department of Neurological Sciences, Christian Medical College Hospital, Vellore 632 004, India.
28. Department of Neurology, Oregon Health &Science University, Portland, Oregon 97239, USA.
29. Department of Pediatrics, Oregon Health &Science University, Portland, Oregon 97239, USA.

Abstract

Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.