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.

Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

“…Mutations in the Mn transporters SLC39A14 and SLC30A10 have been associated with increased Mn levels in the serum and brain [4, 30] and the development of PD-like symptoms. Moreover, exposure to occupational and other environmental sources of high Mn can cause similar neurological symptoms [50, 51].…”

Aging amplifies multiple phenotypic defects in mice with zinc transporter Zip14 (Slc39a14) deletion

“…It has been proposed that the large number of zinc transporters is necessitated because of the plethora of intracellular functions in which this essential micronutrient participates (Lichten and Cousins, 2009a). Examples for the ZIP transporters/disease relationship include adipose inflammation and ZIP14 (Troche et al, 2016), ZIP8 and ZIP14 and response to sepsis (Knoell et al, 2009; Wessels and Cousins, 2015), ZIP13 and Ehlers-Danlos syndrome (Jeong et al, 2012), ZIP14 and metabolic endotoxemia (Guthrie et al, 2015), ZIP8 and osteoarthritis (Kim et al, 2014) and mutant Zip14 and parkinsonism/dystonia (Tuschi et al, 2016). One report that relates ZIP transporter function to aging was an evaluation of Zip6 mRNA expression in immune cells (Wong et al, 2013).…”

“…We cannot rule out the involvement of another ZIP14-regulated process in the loss of trabecular bone in the aged Zip14 KO mice. It has been postulated, based on in vitro transfection studies and data from zebrafish, that the major role for ZIP14 is to transport Mn (Tuschl et al, 2016). If that hypothesis is correct, ZIP14 dysfunction could reduce biliary Mn elimination, causing Mn retention in the brain leading to neurological disorders.…”

Hepatic metal ion transporter ZIP8 regulates manganese homeostasis and manganese-dependent enzyme activity

“…ZIP14, a close family member of ZIP8, may be responsible for the uptake of Mn from blood, as it has been reported to be localized on the basolateral membrane of hepatocytes (35) and has affinity for Mn in vitro (28,36). Furthermore, patients carrying SLC39A14 mutations showed excessive Mn accumulation in the whole blood and brain but a lack of Mn in the liver, possibly due to the bypassing of hepatic uptake by Mn and subsequent biliary excretion in the absence of SLC39A14 (37). SLC30A10, a Mn exporter, is expressed in the liver and may be the transporter that excretes Mn from hepatocytes into the bile canaliculi (26).…”