The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.
SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel cerebro-renal syndrome
Open accessAbstract
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 the six affected individuals also had 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 an ∼18 Mb disease-associated locus on chromosome 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 state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to 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 signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9's highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration 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 activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A mutation in the fourth TMD in SLC30A9 was found to cause acute dysregulation of zinc homeostasis in all family members affected by a novel cerebro-renal syndrome with important early neurological deterioration.
“Previously, a mutation in the fourth TMD in SLC30A9 was found to cause acute dysregulation of zinc homeostasis in all family members affected by a novel cerebro-renal syndrome with important early neurological deterioration [54].”
From Human genetic adaptation related to cellular zinc homeostasis (2023) · cites this paper as [54]
The Results (Protein structural predictions and functional analysis; page unavailable) place the mutation in the fourth transmembrane helix and report reduced cytosolic free zinc in cells expressing mutant SLC30A9. The Results (Clinical characterization; page unavailable) describe early neurological deterioration in all six affected individuals. The zinc finding came from transfected cells, not measurements in every affected family member, and the paper does not characterize the dysregulation as acute. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSLC30A9 is moderately expressed in most tissues, but its expression is higher in fetal brain, cerebellum, skeletal muscle, pituitary, thyroid, and kidneys.
“Although SLC30A9 is moderately expressed in most tissues, its expression is higher in the fetal brain, cerebellum, skeletal muscle, pituitary, thyroid, and kidneys [54].”
From Human genetic adaptation related to cellular zinc homeostasis (2023) · cites this paper as [54]
The Results section, “SLC30A9 expression patterns and subcellular localization” (page unavailable), says SLC30A9 is moderately expressed in most tissues examined and highly transcribed in foetal brain, cerebellum, skeletal muscle, and kidney. It does not identify pituitary or thyroid as tissues with higher expression. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576
SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling
Guex, N., & Peitsch, M. C. (1997) · Electrophoresis · doi:10.1002/elps.1150181505 · Cited by 11,297
A genome-wide association study identifies novel risk loci for type 2 diabetes
Sladek, R., Rocheleau, G., Rung, J., Dina, C., Shen, L., Serre, D., Boutin, P., Vincent, D., Belisle, A., Hadjadj, S., et al. (2007) · Nature · doi:10.1038/nature05616 · Cited by 2,993
Zinc homeostasis and signaling in health and diseases
Fukada, T., Yamasaki, S., Nishida, K., Murakami, M., & Hirano, T. (2011) · JBIC Journal of Biological Inorganic Chemistry · doi:10.1007/s00775-011-0797-4 · Cited by 608
Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, and KCNJ10 Mutations
Böckenhauer, D., Feather, S. A., Stanescu, H. C., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810276 · Cited by 594
Genetically encoded FRET sensors to monitor intracellular Zn2+ homeostasis
Vinkenborg, J. L., Nicolson, T. J., Bellomo, E. A., Koay, M. S. T., Rutter, G. A., & Merkx, M. (2009) · Nature Methods · doi:10.1038/nmeth.1368 · Cited by 433
Self-citationNephronophthisis-Associated Ciliopathies
Hildebrandt, F., & Zhou, W. (2007) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006121344 · Cited by 418
Quadri, M., Federico, A., Zhao, T., Breedveld, G. J., Battisti, C., Delnooz, C. C. S., Severijnen, L.-A. W. F. M., Mammarella, L. D. T., Mignarri, A., Monti, L., et al. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.01.017 · Cited by 416
Structure of the Zinc Transporter YiiP
Lu, M., & Fu, D. (2007) · Science · doi:10.1126/science.1143748 · Cited by 386
Nicolson, T. J., Bellomo, E. A., Wijesekara, N., Loder, M. K., Baldwin, J. M., Gyulkhandanyan, A. V., Koshkin, V., Tarasov, A. I., Carzaniga, R., Kronenberger, K., et al. (2009) · Diabetes · doi:10.2337/db09-0551 · Cited by 372
Self-citationHomozygosityMapper--an interactive approach to homozygosity mapping
Seelow, D., Schuelke, M., Hildebrandt, F., & Nürnberg, P. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp369 · Cited by 365
Chowanadisai, W., Lönnerdal, B., & Kelleher, S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605821200 · Cited by 278
The GPN Study Group, Halbritter, J., Porath, J. D., Diaz, K. A., Braun, D. A., Kohl, S., Chaki, M., Allen, S. J., Soliman, N. A., Hildebrandt, F., et al. (2013) · Human Genetics · doi:10.1007/s00439-013-1297-0 · Cited by 243
Cation Diffusion Facilitator family: Structure and function
Kolaj‐Robin, O., Russell, D. H., Hayes, K. A., Pembroke, J. T., & Soulimane, T. (2015) · FEBS Letters · doi:10.1016/j.febslet.2015.04.007 · Cited by 202
Nephronophthisis and related syndromes
Wolf, M. T. F. (2015) · Current Opinion in Pediatrics · doi:10.1097/mop.0000000000000194 · Cited by 159
The oculocerebrorenal syndrome of Lowe: an update
Bökenkamp, A., & Ludwig, M. Z. (2016) · Pediatric Nephrology · doi:10.1007/s00467-016-3343-3 · Cited by 151
Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ
Barel, O., Shorer, Z., Flusser, H., Ofir, R., Narkis, G., Finer, G., Shalev, H., Nasasra, A. E., Saada, A., & Birk, O. S. (2008) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2008.03.020 · Cited by 143
Self-citationZinc: indications in brain disorders
Prakash, A. K., Bharti, K., & Majeed, A. B. A. (2015) · Fundamental and Clinical Pharmacology · doi:10.1111/fcp.12110 · Cited by 131
Hoch, E., Lin, W., Chai, J. L., Hershfinkel, M., Fu, D., & Sekler, I. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1200362109 · Cited by 129
Mitochondrial and ER-Targeted eCALWY Probes Reveal High Levels of Free Zn2+
CHABOSSEAU, P. L., Tuncay, E., Meur, G., Bellomo, E. A., Hessels, A. M., Hughes, S. J., Johnson, P., Bugliani, M., Marchetti, P., Turan, B., et al. (2014) · ACS Chemical Biology · doi:10.1021/cb5004064 · Cited by 117
Self-citationAction myoclonus-renal failure syndrome: characterization of a unique cerebro-renal disorder
Badhwar, A. (2004) · Brain · doi:10.1093/brain/awh263 · Cited by 98
Nishito, Y., Tsuji, N., Fujishiro, H., Takeda, T.-A., Yamazaki, T., Teranishi, F., Okazaki, F., Matsunaga, A., Tuschl, K., Rao, R., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.728014 · Cited by 94
Haider, N. B., Carmi, R., Shalev, H., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/302108 · Cited by 89
Self-citationSilberstein, M., Tzemach, A., Dovgolevsky, N., Fishelson, M., Schuster, A., & Geiger, D. (2006) · The American Journal of Human Genetics · doi:10.1086/504158 · Cited by 88
GAC63, a GRIP1-Dependent Nuclear Receptor Coactivator
Chen, Y., Kim, J. H., & Stallcup, M. R. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.14.5965-5972.2005 · Cited by 77
Inflammation, genes and zinc in ageing and age-related diseases
Vasto, S., Mocchegiani, E., Candore, G., Listı̀, F., Colonna‐Romano, G., Lio, D., Malavolta, M., Giacconi, R., Cipriano, C., & Caruso, C. (2006) · Biogerontology · doi:10.1007/s10522-006-9046-6 · Cited by 64
Perez, Y., Kadir, R., Volodarsky, M., et al. (2015) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2015-103352 · Cited by 62
Self-citationZinc Transporter mRNA Levels in Alzheimer's Disease Postmortem Brain
Beyer, N., Coulson, D. T. R., Heggarty, S., Ravid, R., Hellemans, J., Irvine, G. B., & Johnston, J. A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-112105 · Cited by 55
Tyszka‐Czochara, M., Grzywacz, A., Gdula‐Argasińska, J., Librowski, T., Wiliński, B., & Opoka, W. (2014) · PubMed · Cited by 55
Phylogenomic analysis of Cation Diffusion Facilitator proteins uncovers Ni2+/Co2+ transporters
Cubillas, C. A., Vinuesa, P., Tabche, M. L., et al. (2013) · Metallomics · doi:10.1039/c3mt00204g · Cited by 52
Lobo, J. C., Torres, J. P. M., Fouque, D. P., & Mafra, D. (2009) · Biological Trace Element Research · doi:10.1007/s12011-009-8504-9 · Cited by 49
Role of GAC63 in transcriptional activation mediated by -catenin
Chen, Y., Yang, C.-H., Xia, M., Ou, C. Y., & Stallcup, M. R. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm095 · Cited by 28
Renal function and mitochondrial cytopathy (MC): more questions than answers?
Hall, A. M., Unwin, R. J., Hanna, M. G., & Duchen, M. R. (2008) · QJM · doi:10.1093/qjmed/hcn060 · Cited by 26
Deciphering the fine-structure of tribal admixture in the Bedouin population using genomic data
Markus, B., Alshafee, I., & Birk, O. S. (2013) · Heredity · doi:10.1038/hdy.2013.90 · Cited by 25
Self-citationRole of GAC63 in transcriptional activation mediated by beta‐catenin
Chen, Y., Yang, C. K., Xia, M., Ou, C. Y., & Stallcup, M. R. (2007) · The FASEB Journal · doi:10.1096/fasebj.21.5.a284-c · Cited by 7
Severe tubular resistance to aldosterone in a child with familial juvenile nephronophthisis
Eisenstein, B., Davidovitz, M., Garty, B. Z., et al. (1992) · Pediatric Nephrology · doi:10.1007/bf00856835 · Cited by 7
Flagged first, then by citations
Cited by
Sorted by citations
Human genetic adaptation related to cellular zinc homeostasis
Roca-Umbert, A., Garcia-Calleja, J., Vogel-González, M., Fierro-Villegas, A., Ill-Raga, G., Herrera-Fernández, V., Bosnjak, A., Muntané, G., Gutiérrez, E., Campelo, F., et al. (2023) · PLoS Genetics · doi:10.1371/journal.pgen.1010950 · Cited by 8
Metadata
- Authors
- Perez, Y., Shorer, Z., Liani-Leibson, K., Chabosseau, P., Kadir, R., Volodarsky, M., Halperin, D., Barber-Zucker, S., Shalev, H., Schreiber, R., Gradstein, L., Gurevich, E., Zarivach, R., Rutter, G. A., Landau, D., & Birk, O. S.
- Affiliations
- Ben-Gurion University of the Negev (IL)
- Imperial College London (GB)
- Corresponding author
- Birk, Ohad S.
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-02-09
- Volume
- 140
- Issue
- 4
- Pages
- 928-939
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5837213
- OpenAlex
- W2603980184
- Cited by
- 99
- References
- 37
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 11 · 2023: 11 · 2022: 14 · 2021: 11 · 2020: 10 · 2019: 6 · 2018: 9 · 2017: 7
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (WT098424AIA)
- Diabetes UK (BDA15/0005275)
- Ministry of Science, Technology and Space
- Israel Science Foundation (761676, 1814/13, 1798/16)
- Directorate for Biological Sciences
- Medical Research Council (MR/K001981/1, MR/J0003042/1)
- Biotechnology and Biological Sciences Research Council (BB/J015873/1)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autosomal recessive disorder, consanguinity, Bedouin, zinc transporters, Wnt signaling, interstitial nephritis, intellectual disability, ataxia, oculomotor apraxia, endoplasmic reticulum localization, protein modeling, linkage analysis
- MeSH terms
- Chromosome Mapping, Consanguinity, Cytosol, Female, Homeostasis, Humans, Infant, Kidney Diseases, Male, Intellectual Disability, Mutation, Nuclear Proteins, Pedigree, Syndrome, Transcription Factors, Zinc, Hereditary Sensory and Motor Neuropathy, Age of Onset, Cell Cycle Proteins, Arabs, Cation Transport Proteins, Genome-Wide Association Study, HEK293 Cells, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
