Maintaining Translational Relevance in Animal Models of Manganese Neurotoxicity

ABSTRACT Manganese is an essential metal, but elevated brain Mn concentrations produce a parkinsonian-like movement disorder in adults and fine motor, attentional, cognitive, and intellectual deficits in children. Human Mn neurotoxicity occurs owing to elevated exposure from occupational or environmental sources, defective excretion (e.g., due to cirrhosis), or loss-of-function mutations in the Mn transporters solute carrier family 30 member 10 or solute carrier family 39 member 14. Animal models are essential to study Mn neurotoxicity, but in order to be translationally relevant, such models should utilize environmentally relevant Mn exposure regimens that reproduce changes in brain Mn concentrations and neurological function evident in human patients. Here, we provide guidelines for Mn exposure in mice, rats, nematodes, and zebrafish so that brain Mn concentrations and neurobehavioral sequelae remain directly relatable to the human phenotype.

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Maternal Primary Carnitine Deficiency and a Novel Solute Carrier Family 22 Member 5 (SLC22A5) Mutation

Journal of Investigative Medicine High Impact Case Reports ◽

10.1177/23247096211019543 ◽

2021 ◽

Vol 9 ◽

pp. 232470962110195

Author(s):

Michael Jakoby ◽

Amruta Jaju ◽

Aundrea Marsh ◽

Andrew Wilber

Keyword(s):

Stop Codon ◽

Premature Stop Codon ◽

Thyroid Stimulating Hormone ◽

Carnitine Deficiency ◽

Reproductive Age ◽

Acid Oxidation ◽

Solute Carrier Family ◽

Loss Of Function ◽

Solute Carrier ◽

Primary Carnitine Deficiency

Primary carnitine deficiency (PCD) is a rare autosomal recessive disorder caused by loss of function mutations in the solute carrier family 22 member 5 ( SLC22A5) gene that encodes a high-affinity sodium-ion–dependent organic cation transporter protein (OCTN2). Reduced carnitine transport results in diminished fatty acid oxidation in heart and skeletal muscle and carnitine wasting in urine. We present a case of PCD diagnosed in an adult female after a positive newborn screen (NBS) for PCD that was not confirmed on follow-up testing. The mother was referred for evaluation of persistent fatigue and possible hypothyroidism even though all measurements of thyroid-stimulating hormone were well within the range of 0.4 to 2.5 mIU/L expected for reproductive-age women. She was found to have unequivocally low levels of both total carnitine and carnitine esters, and genetic testing revealed compound heterozygosity for 2 SLC22A5 mutations. One mutation (c.34G>A [p.Gly12Ser]) is a known missense mutation with partial OCTN2 activity, but the other mutation (c.41G>A [p.Trp14Ter]) is previously unreported and results in a premature stop codon and truncated OCTN2. This case illustrates that some maternal inborn errors of metabolism can be identified by NBS and that maternal carnitine levels should be checked after a positive NBS test for PCD.

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Incomplete glycosylation and defective intracellular targeting of mutant solute carrier family 11 member 1 (Slc11a1)

Biochemical Journal ◽

10.1042/bj20040808 ◽

2004 ◽

Vol 382 (3) ◽

pp. 811-819 ◽

Cited By ~ 19

Author(s):

Jacqueline K. WHITE ◽

Abigail STEWART ◽

Jean-Francois POPOFF ◽

Shona WILSON ◽

Jenefer M. BLACKWELL

Keyword(s):

Immunoelectron Microscopy ◽

Leishmania Donovani ◽

Transmembrane Domain ◽

Solute Carrier Family ◽

Loss Of Function ◽

Wild Type ◽

Bivalent Cation ◽

Intracellular Targeting ◽

Solute Carrier ◽

Heterologous Expression Systems

Solute carrier family 11 member 1 (Slc11a1, formerly Nramp1) is a highly glycosylated, 12 transmembrane domain protein expressed in macrophages. It resides in the membrane of late endosomes and lysosomes, where it functions as a bivalent cation transporter. Mice susceptible to infection by various intracellular pathogens including Leishmania donovani and Salmonella typhimurium carry a glycine to aspartic acid substitution at position 169 (G169D, Gly169→Asp), within transmembrane domain 4 of Slc11a1. To investigate the molecular pathogenesis of infectious disease susceptibility, we compared the behaviour of heterologously and endogenously expressed wild-type and mutant Slc11a1 by immunofluorescence, immunoelectron microscopy and Western-blot analysis. We found occasional late endosome/lysosome staining of mutant protein using immunoelectron microscopy, but most of the mutant Slc11a1 was retained within the ER (endoplasmic reticulum). Using glycosylation as a marker for protein maturation in two independent heterologous expression systems, we found that most mutant Slc11a1 existed as an ER-dependent, partially glycosylated intermediate species. Correct endosomal targeting of wild-type Slc11a1 continued despite disruption of N-glycosylation sites, indicating that glycosylation did not influence folding or sorting. We propose that the G169D mutation causes localized misfolding of Slc11a1, resulting in its retention in the ER and manifestation of the loss of function phenotype.

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SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1720739115 ◽

2018 ◽

Vol 115 (8) ◽

pp. E1769-E1778 ◽

Cited By ~ 43

Author(s):

Supak Jenkitkasemwong ◽

Adenike Akinyode ◽

Elizabeth Paulus ◽

Ralf Weiskirchen ◽

Shintaro Hojyo ◽

...

Keyword(s):

Early Life ◽

Motor Deficits ◽

Iron Loading ◽

Solute Carrier Family ◽

Motor Impairments ◽

Liver And Pancreas ◽

Solute Carrier ◽

The Brain ◽

Iron And Manganese ◽

Mn Concentrations

Solute carrier family 39, member 14 (SLC39A14) is a transmembrane transporter that can mediate the cellular uptake of zinc, iron, and manganese (Mn). Studies of Slc39a14 knockout (Slc39a14−/−) mice have documented that SLC39A14 is required for systemic growth, hepatic zinc uptake during inflammation, and iron loading of the liver in iron overload. The normal physiological roles of SLC39A14, however, remain incompletely characterized. Here, we report that Slc39a14−/− mice spontaneously display dramatic alterations in tissue Mn concentrations, suggesting that Mn is a main physiological substrate for SLC39A14. Specifically, Slc39a14−/− mice have abnormally low Mn levels in the liver coupled with markedly elevated Mn concentrations in blood and most other organs, especially the brain and bone. Radiotracer studies using 54Mn reveal that Slc39a14−/− mice have impaired Mn uptake by the liver and pancreas and reduced gastrointestinal Mn excretion. In the brain of Slc39a14−/− mice, Mn accumulated in the pons and basal ganglia, including the globus pallidus, a region susceptible to Mn-related neurotoxicity. Brain Mn accumulation in Slc39a14−/− mice was associated with locomotor impairments, as assessed by various behavioral tests. Although a low-Mn diet started at weaning was able to reverse brain Mn accumulation in Slc39a14−/− mice, it did not correct their motor deficits. We conclude that SLC39A14 is essential for efficient Mn uptake by the liver and pancreas, and its deficiency results in impaired Mn excretion and accumulation of the metal in other tissues. The inability of Mn depletion to correct the motor deficits in Slc39a14−/− mice suggests that the motor impairments represent lasting effects of early-life Mn exposure.

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Fine mapping* of the bovine solute carrier family 25, member 4 (SLC25A4) gene to BTA27q14-q15 by fluorescence in situ hybridization and radiation hybrid mapping

Animal Genetics ◽

10.1046/j.1365-2052.2002.t01-15-00886.x ◽

2002 ◽

Vol 33 (4) ◽

pp. 318-320

Author(s):

C. Drogemuller ◽

H. Kuiper ◽

G. Hauke ◽

J. L. Williams ◽

O. Distl

Keyword(s):

In Situ Hybridization ◽

Fluorescence In Situ Hybridization ◽

Fine Mapping ◽

Radiation Hybrid ◽

Radiation Hybrid Mapping ◽

Solute Carrier Family ◽

Hybrid Mapping ◽

Solute Carrier

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Autosomal recessive congenital hereditary corneal dystrophy associated with a novel SLC4A11 mutation in two consanguineous Tunisian families

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2020-318204 ◽

2021 ◽

pp. bjophthalmol-2020-318204

Author(s):

Zohra Chibani ◽

Imen Zone Abid ◽

Peter Söderkvist ◽

Jamel Feki ◽

Mounira Hmani Aifa

Keyword(s):

Autosomal Recessive ◽

Corneal Transplantation ◽

Gene Mutations ◽

In Silico Analysis ◽

Corneal Dystrophy ◽

Solute Carrier Family ◽

Transporter Protein ◽

Bicarbonate Transporter ◽

Corneal Clouding ◽

Solute Carrier

BackgroundAutosomal recessive congenital hereditary corneal dystrophy (CHED) is a rare isolated developmental anomaly of the eye characterised by diffuse bilateral corneal clouding that may lead to visual impairment requiring corneal transplantation. CHED is known to be caused by mutations in the solute carrier family 4 member 11 (SLC4A11) gene which encodes a membrane transporter protein (sodium bicarbonate transporter-like solute carrier family 4 member 11).MethodsTo identify SLC4A11 gene mutations associated with CHED (OMIM: #217700), genomic DNA was extracted from whole blood and sequenced for all exons and intron-exon boundaries in two large Tunisian families.ResultsA novel deletion SLC4A11 mutation (p. Leu479del; c.1434_1436del) is responsible for CHED in both analysed families. This non-frameshift mutation was found in a homozygous state in affected members and heterozygous in non-affected members. In silico analysis largely support the pathogenicity of this alteration that may leads to stromal oedema by disrupting the osmolarity balance. Being localised to a region of alpha-helical secondary structure, Leu479 deletion may induce protein-compromising structural rearrangements.ConclusionTo the best of our knowledge, this is the first clinical and genetic study exploring CHED in Tunisia. The present work also expands the list of pathogenic genotypes in SLC4A11 gene and its associated clinical diagnosis giving more insights into genotype–phenotype correlations.

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Slc7a11 Modulated by POU2F1 is Involved in Pigmentation in Rabbit

International Journal of Molecular Sciences ◽

10.3390/ijms20102493 ◽

2019 ◽

Vol 20 (10) ◽

pp. 2493 ◽

Cited By ~ 4

Author(s):

Yang Chen ◽

Shuaishuai Hu ◽

Lin Mu ◽

Bohao Zhao ◽

Manman Wang ◽

...

Keyword(s):

Skin Color ◽

Site Directed Mutagenesis ◽

Molecular Regulation ◽

Luciferase Reporter ◽

Directed Mutagenesis ◽

Regulation Mechanism ◽

Solute Carrier Family ◽

Depth Analysis ◽

Solute Carrier ◽

Fur Color

Solute carrier family 7 member 11 (Slc7a11) is a cystine/glutamate xCT transporter that controls the production of pheomelanin pigment to change fur and skin color in animals. Previous studies have found that skin expression levels of Slc7a11 varied significantly with fur color in Rex rabbits. However, the molecular regulation mechanism of Slc7a11 in pigmentation is unknown. Here, rabbit melanocytes were first isolated and identified. The distribution and expression pattern of Slc7a11 was confirmed in skin from rabbits with different fur colors. Slc7a11 affected the expression of pigmentation related genes and thus affected melanogenesis. Meanwhile, Slc7a11 decreased melanocyte apoptosis, but inhibition of Slc7a11 enhanced apoptosis. Furthermore, the POU2F1 protein was found to bind to the −713 to −703 bp region of Slc7a11 promoter to inhibit its activity in a dual-luciferase reporter and site-directed mutagenesis assay. This study reveals the function of the Slc7a11 in melanogenesis and provides in-depth analysis of the mechanism of fur pigmentation.

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