SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome

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Title: SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome
Authors: Perez, Y
Leibson, K
Chabosseau, P
Kadir, R
Volodarsky, M
Halperin, D
Barber-Zucker, S
Shalev, S
Schreiber, R
Gradstein, L
Gurevich, E
Zarivach, R
Rutter, GA
Landau, D
Birk, OS
Item Type: Journal Article
Abstract: A novel autosomal recessive cerebro - renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of t he six affected individuals had also early - onset nephropathy with features of tubulo - interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified a ~ 18Mbs disease - associated locus on chro mosome 4 ( maximal logarithm of odds score 4.4 at D4S2971 ; θ =0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus , segregating as expected within the kindred and not found in a homozygous s tate in 300 Bedouin controls . We showed that SLC30A9 (Solute Carrier Family 30 , Member 9 ; ZnT - 9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH - SY5Y cells overexpressing SLC30A9 fused t o enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum , not co - localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signaling. However, using d ual - l uciferase r eporter a ssay in SH - SY5Y cells we showed that Wnt signaling was not affected by the mutation. Based on protein modeling, the iden tified mutation is expected to affect SLC30A9’s highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn 2+ measurements in HEK293 cells overexpressing wild - type and mutant SLC30A9 showed lower zinc concen tration within mutant rather than wild - type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activi ty of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signaling.
Issue Date: 9-Feb-2017
Date of Acceptance: 16-Dec-2016
ISSN: 0006-8950
Publisher: Oxford University Press
Start Page: 928
End Page: 939
Journal / Book Title: Brain
Volume: 140
Issue: 4
Copyright Statement: The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Wellcome Trust
Funder's Grant Number: 098424/Z/12/ZR
Keywords: Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences & Neurology
Cerebro-renal syndrome
neurodevelopmental regression
zinc homeostasis
Age of Onset
Cation Transport Proteins
Cell Cycle Proteins
Chromosome Mapping
Genome-Wide Association Study
HEK293 Cells
Hereditary Sensory and Motor Neuropathy
Intellectual Disability
Kidney Diseases
Nuclear Proteins
Wnt Signaling Pathway
11 Medical And Health Sciences
17 Psychology And Cognitive Sciences
Neurology & Neurosurgery
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine

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