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

Karin Tuschl; Esther Meyer; Leonardo E. Valdivia; Ningning Zhao; Chris Dadswell; Alaa Abdul-Sada; Christina Y. Hung; Michael A. Simpson; W. K. Chong; Thomas S. Jacques; Randy L. Woltjer; Simon Eaton; Allison Gregory; Lynn Sanford; Eleanna Kara; Henry Houlden; Stephan M. Cuno; Holger Prokisch; Lorella Valletta; Valeria Tiranti; Rasha Younis; Eamonn R. Maher; John Spencer; Ania Straatman-Iwanowska; Paul Gissen; Laila A.M. Selim; Guillem Pintos-Morell; Wifredo Coroleu-Lletget; Shekeeb S. Mohammad; Sangeetha Yoganathan; Russell C. Dale; Maya Thomas; Jason Rihel; Olaf A. Bodamer; Caroline A. Enns; Susan J. Hayflick; Peter T. Clayton; Philippa B. Mills; Manju A. Kurian; Stephen W. Wilson

doi:https://doi.org/10.1038/ncomms11601

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

Karin Tuschl, Esther Meyer, Leonardo E. Valdivia, Ningning Zhao, Chris Dadswell, Alaa Abdul-Sada, Christina Y. Hung, Michael A. Simpson, W. K. Chong, Thomas S. Jacques, Randy L. Woltjer, Simon Eaton, Allison Gregory, Lynn Sanford, Eleanna Kara, Henry Houlden, Stephan M. Cuno, Holger Prokisch, Lorella Valletta, Valeria TirantiRasha Younis, Eamonn R. Maher, John Spencer, Ania Straatman-Iwanowska, Paul Gissen, Laila A.M. Selim, Guillem Pintos-Morell, Wifredo Coroleu-Lletget, Shekeeb S. Mohammad, Sangeetha Yoganathan, Russell C. Dale, Maya Thomas, Jason Rihel, Olaf A. Bodamer, Caroline A. Enns, Susan J. Hayflick, Peter T. Clayton, Philippa B. Mills, Manju A. Kurian, Stephen W. Wilson

Department of Paediatrics, Obstetrics and Gynaecology and Preventive Medicine and Public Health

Research output: Contribution to journal › Article › Research › peer-review

151 Citations (Scopus)

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.

Original language	English
Article number	11601
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11601
Publication status	Published - 27 May 2016

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Tuschl, K., Meyer, E., Valdivia, L. E., Zhao, N., Dadswell, C., Abdul-Sada, A., Hung, C. Y., Simpson, M. A., Chong, W. K., Jacques, T. S., Woltjer, R. L., Eaton, S., Gregory, A., Sanford, L., Kara, E., Houlden, H., Cuno, S. M., Prokisch, H., Valletta, L., ... Wilson, S. W. (2016). Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nature Communications, 7, [11601]. https://doi.org/10.1038/ncomms11601

Tuschl, Karin ; Meyer, Esther ; Valdivia, Leonardo E. ; Zhao, Ningning ; Dadswell, Chris ; Abdul-Sada, Alaa ; Hung, Christina Y. ; Simpson, Michael A. ; Chong, W. K. ; Jacques, Thomas S. ; Woltjer, Randy L. ; Eaton, Simon ; Gregory, Allison ; Sanford, Lynn ; Kara, Eleanna ; Houlden, Henry ; Cuno, Stephan M. ; Prokisch, Holger ; Valletta, Lorella ; Tiranti, Valeria ; Younis, Rasha ; Maher, Eamonn R. ; Spencer, John ; Straatman-Iwanowska, Ania ; Gissen, Paul ; Selim, Laila A.M. ; Pintos-Morell, Guillem ; Coroleu-Lletget, Wifredo ; Mohammad, Shekeeb S. ; Yoganathan, Sangeetha ; Dale, Russell C. ; Thomas, Maya ; Rihel, Jason ; Bodamer, Olaf A. ; Enns, Caroline A. ; Hayflick, Susan J. ; Clayton, Peter T. ; Mills, Philippa B. ; Kurian, Manju A. ; Wilson, Stephen W. / Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. In: Nature Communications. 2016 ; Vol. 7.

@article{f423a45fb2c64c69972f945cbf9220e3,

title = "Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia",

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.",

author = "Karin Tuschl and Esther Meyer and Valdivia, {Leonardo E.} and Ningning Zhao and Chris Dadswell and Alaa Abdul-Sada and Hung, {Christina Y.} and Simpson, {Michael A.} and Chong, {W. K.} and Jacques, {Thomas S.} and Woltjer, {Randy L.} and Simon Eaton and Allison Gregory and Lynn Sanford and Eleanna Kara and Henry Houlden and Cuno, {Stephan M.} and Holger Prokisch and Lorella Valletta and Valeria Tiranti and Rasha Younis and Maher, {Eamonn R.} and John Spencer and Ania Straatman-Iwanowska and Paul Gissen and Selim, {Laila A.M.} and Guillem Pintos-Morell and Wifredo Coroleu-Lletget and Mohammad, {Shekeeb S.} and Sangeetha Yoganathan and Dale, {Russell C.} and Maya Thomas and Jason Rihel and Bodamer, {Olaf A.} and Enns, {Caroline A.} and Hayflick, {Susan J.} and Clayton, {Peter T.} and Mills, {Philippa B.} and Kurian, {Manju A.} and Wilson, {Stephen W.}",

year = "2016",

month = may,

day = "27",

doi = "https://doi.org/10.1038/ncomms11601",

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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, LAM, 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 2016, 'Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia', Nature Communications, vol. 7, 11601. https://doi.org/10.1038/ncomms11601

Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. / Tuschl, Karin; Meyer, Esther; Valdivia, Leonardo E.; Zhao, Ningning; Dadswell, Chris; Abdul-Sada, Alaa; Hung, Christina Y.; Simpson, Michael A.; Chong, W. K.; Jacques, Thomas S.; Woltjer, Randy L.; Eaton, Simon; Gregory, Allison; Sanford, Lynn; Kara, Eleanna; Houlden, Henry; Cuno, Stephan M.; Prokisch, Holger; Valletta, Lorella; Tiranti, Valeria; Younis, Rasha; Maher, Eamonn R.; Spencer, John; Straatman-Iwanowska, Ania; Gissen, Paul; Selim, Laila A.M.; Pintos-Morell, Guillem; Coroleu-Lletget, Wifredo; Mohammad, Shekeeb S.; Yoganathan, Sangeetha; Dale, Russell C.; Thomas, Maya; Rihel, Jason; Bodamer, Olaf A.; Enns, Caroline A.; Hayflick, Susan J.; Clayton, Peter T.; Mills, Philippa B.; Kurian, Manju A.; Wilson, Stephen W.

In: Nature Communications, Vol. 7, 11601, 27.05.2016.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia

AU - Tuschl, Karin

AU - Meyer, Esther

AU - Valdivia, Leonardo E.

AU - Zhao, Ningning

AU - Dadswell, Chris

AU - Abdul-Sada, Alaa

AU - Hung, Christina Y.

AU - Simpson, Michael A.

AU - Chong, W. K.

AU - Jacques, Thomas S.

AU - Woltjer, Randy L.

AU - Eaton, Simon

AU - Gregory, Allison

AU - Sanford, Lynn

AU - Kara, Eleanna

AU - Houlden, Henry

AU - Cuno, Stephan M.

AU - Prokisch, Holger

AU - Valletta, Lorella

AU - Tiranti, Valeria

AU - Younis, Rasha

AU - Maher, Eamonn R.

AU - Spencer, John

AU - Straatman-Iwanowska, Ania

AU - Gissen, Paul

AU - Selim, Laila A.M.

AU - Pintos-Morell, Guillem

AU - Coroleu-Lletget, Wifredo

AU - Mohammad, Shekeeb S.

AU - Yoganathan, Sangeetha

AU - Dale, Russell C.

AU - Thomas, Maya

AU - Rihel, Jason

AU - Bodamer, Olaf A.

AU - Enns, Caroline A.

AU - Hayflick, Susan J.

AU - Clayton, Peter T.

AU - Mills, Philippa B.

AU - Kurian, Manju A.

AU - Wilson, Stephen W.

PY - 2016/5/27

Y1 - 2016/5/27

N2 - 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.

AB - 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.

U2 - https://doi.org/10.1038/ncomms11601

DO - https://doi.org/10.1038/ncomms11601

M3 - Article

VL - 7

M1 - 11601

ER -

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

Abstract

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