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

2018 ◽  
Vol 115 (8) ◽  
pp. E1769-E1778 ◽  
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.

scholarly journals Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans

2020 ◽  
Author(s):  
Jamie L. Courtland ◽  
Tyler W. A. Bradshaw ◽  
Greg Waitt ◽  
Erik J. Soderblom ◽  
Tricia Ho ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Retrospective Analysis ◽  
Mouse Brain ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Proteomics Analysis ◽  
Lysosomal Dysfunction ◽  
The Brain ◽  
Progressive Motor Deficits

ABSTRACTMutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

scholarly journals Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

2022 ◽  
Author(s):  
Maricel F. Molina ◽  
Patricia Papendieck ◽  
Gabriela Sobrero ◽  
Viviana A. Balbi ◽  
Fiorella S. Belforte ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Bioinformatic Analysis ◽  
Thyroid Stimulating Hormone ◽  
Motor Deficits ◽  
Thyroid Peroxidase ◽  
Solute Carrier Family ◽  
Dual Oxidase ◽  
Thyroid Dyshormonogenesis ◽  
Solute Carrier ◽  
And Function

Abstract Purpose Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the preventable causes of both cognitive and motor deficits. We present a genetic and bioinformatics investigation of rational clinical design in 16 Argentine patients suspected of CH due to thyroid dyshormonogenesis (TDH). Methods Next-Generation Sequencing approach was used to identify variants in Thyroid Peroxidase (TPO) and Dual Oxidase 2 (DUOX2) genes. A custom panel targeting 7 genes associated with TDH [(TPO, Iodothyrosine Deiodinase I (IYD), Solute Carrier Family 26 Member 4 (SLC26A4), Thyroglobulin (TG), (DUOX2), Dual Oxidase Maturation Factor 2 (DUOXA2), Solute Carrier Family 5 Member 5 (SLC5A5)] and 4 associated with thyroid dysembryogenesis [PAX8, FOXE1, NKX2-1, Thyroid Stimulating Hormone Receptor (TSHR)] has been designed. Additionally, bioinformatic analysis and structural modeling were carried out to predict the disease-causing potential variants. Results Five novel variants have been identified, two in TPO: c.2749-2A>C and c.2752_2753delAG, [p.Ser918Cysfs*62] and three variants in DUOX2 gene: c.425C>G [p.Pro142Arg]; c.790delC [p.Leu264Cysfs*57] and c.2695delC [p.Gln899Serfs*21]. Seventeen identified TPO, DUOX2 and IYD variants were previously described. We identified potentially pahogenic bi-allelic variants in TPO and DUOX2 in 8 and 2 patients, respectively. We also detected a potentially pathogenic mono-allelic variant in TPO and DUOX2 in 4 and 1 patients respectively. Only two patients were heterozygous for digenic variants in TPO/IYD and in TPO/DUOX2 genes. Conclusions 22 variants have been identified associated with TDH. All described novel mutations occur in domains important for protein structure and function, predicting the TDH phenotype.

scholarly journals Maintaining Translational Relevance in Animal Models of Manganese Neurotoxicity

2020 ◽  
Vol 150 (6) ◽  
pp. 1360-1369 ◽  
Author(s):  
Cherish A Taylor ◽  
Karin Tuschl ◽  
Merle M Nicolai ◽  
Julia Bornhorst ◽  
Priscila Gubert ◽  
...  
Keyword(s):  
Animal Models ◽  
Fine Motor ◽  
Solute Carrier Family ◽  
Loss Of Function ◽  
Human Phenotype ◽  
Manganese Neurotoxicity ◽  
Solute Carrier ◽  
Elevated Exposure ◽  
Intellectual Deficits ◽  
Mn Concentrations

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.

scholarly journals Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jamie L Courtland ◽  
Tyler WA Bradshaw ◽  
Greg Waitt ◽  
Erik J Soderblom ◽  
Tricia Ho ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Retrospective Analysis ◽  
Motor Deficits ◽  
Motor Impairments ◽  
Proteomics Analysis ◽  
Lysosomal Dysfunction ◽  
Syndrome Protein ◽  
The Brain ◽  
Progressive Motor Deficits

Mutation of the Wiskott–Aldrich syndrome protein and SCAR homology (WASH) complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. A retrospective analysis of SWIPP1019R patients reveals similar movement deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

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

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.

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A11-A12
Author(s):  
Carolyn Jones ◽  
Randall Olson ◽  
Alex Chau ◽  
Peyton Wickham ◽  
Ryan Leriche ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Early Life ◽  
Autism Spectrum ◽  
Prairie Vole ◽  
Sleep Disruption ◽  
Glutamatergic Synapses ◽  
The Brain ◽  
Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

scholarly journals Slc7a11 Modulated by POU2F1 is Involved in Pigmentation in Rabbit

2019 ◽  
Vol 20 (10) ◽  
pp. 2493 ◽  
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.

scholarly journals Bedside examination of the vestibular and ocular motor system in patients with acute vertigo or dizziness

2019 ◽  
Vol 3 (2) ◽  
pp. 2514183X1988615
Author(s):  
Alexander A Tarnutzer ◽  
Marianne Dieterich
Keyword(s):  
Diagnostic Testing ◽  
Initial Assessment ◽  
Head Impulse Test ◽  
Motor Deficits ◽  
Ocular Motor ◽  
Bedside Examination ◽  
Life Threatening ◽  
Ocular Motor System ◽  
Bedside Tests ◽  
The Brain

In the initial assessment of the patient with acute vertigo or dizziness, both structured history-taking and a targeted bedside neuro-otological examination are essential for distinguishing potentially life-threatening central vestibular causes from those of benign, self-limited peripheral labyrinthine origin and thus for deciding on further diagnostic testing. In this article, the key elements of the vestibular and ocular motor examination, which should be obtained at the bedside in these acutely dizzy patients, will be discussed. Specifically, this will include the following five domains: ocular stability for (I) nystagmus and for (II) eye position (skew deviation), (III) the head-impulse test (HIT), (IV) postural stability, and (V) ocular motor deficits of saccades, smooth pursuit eye movements, and optokinetic nystagmus. We will also discuss the diagnostic accuracy of specific combinations of these bedside tests (i.e. HIT, testing for nystagmus and vertical divergence, referred to as the H.I.N.T.S. three-step examination), emphasizing that the targeted neuro-otological bedside examination is more sensitive for identifying central causes in acute prolonged vertigo and dizziness than early MRI of the brain.

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