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: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

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

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

Keywords

Adolescent
Animals
Cation Transport Proteins/genetics
Child
Child, Preschool
Dystonic Disorders/genetics
Female
Genetic Predisposition to Disease/genetics
HEK293 Cells
Homeostasis
Humans
Male
Manganese/blood
Mutation
Parkinsonian Disorders/genetics
Pedigree
Young Adult
Zebrafish/embryology

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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, Article 11601. https://doi.org/10.1038/ncomms11601

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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.",

keywords = "Adolescent, Animals, Cation Transport Proteins/genetics, Child, Child, Preschool, Dystonic Disorders/genetics, Female, Genetic Predisposition to Disease/genetics, HEK293 Cells, Homeostasis, Humans, Male, Manganese/blood, Mutation, Parkinsonian Disorders/genetics, Pedigree, Young Adult, Zebrafish/embryology",

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 = "10.1038/ncomms11601",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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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

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.

KW - Adolescent

KW - Animals

KW - Cation Transport Proteins/genetics

KW - Child

KW - Child, Preschool

KW - Dystonic Disorders/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - HEK293 Cells

KW - Homeostasis

KW - Humans

KW - Male

KW - Manganese/blood

KW - Mutation

KW - Parkinsonian Disorders/genetics

KW - Pedigree

KW - Young Adult

KW - Zebrafish/embryology

UR - https://www.nature.com/articles/ncomms11601

U2 - 10.1038/ncomms11601

DO - 10.1038/ncomms11601

M3 - Article

C2 - 27231142

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11601

ER -

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

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Keywords

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