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 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

College of Health and Life Sciences

University College London
Oregon Health &Sciences University
University of Sussex
Boston Children's Hospital and Harvard Medical School
King's College London
Great Ormond Street Hospital NHS Foundation Trust
UCL Institute of Child Health and Department of Histopathology
Oregon Health and Science University
Rheinische Friedrich-Wilhelms-Universität Bonn
Foundation Neurological Institute 'C. Besta'
University of Birmingham
Cairo University Children's Hospital
Germans Trias i Pujol University Hospital
University of Sydney
Christian Medical College Hospital

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

280 Citations (SciVal)

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

@article{f033e2ce87594926a7e50407bb6a941a,

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 Research",

}

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

Abstract

Keywords

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