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Alina Ilie, Andy Y L Gao, Jonathan Reid, Annie Boucher, Cassandra McEwan, Hervé Barrière, Gergely L Lukacs, R Anne McKinney, John Orlowski
BACKGROUND: Christianson Syndrome, a recently identified X-linked neurodevelopmental disorder, is caused by mutations in the human gene SLC9A6 encoding the recycling endosomal alkali cation/proton exchanger NHE6. The patients have pronounced limitations in cognitive ability, motor skills and adaptive behaviour. However, the mechanistic basis for this disorder is poorly understood as few of the more than 20 mutations identified thus far have been studied in detail. METHODS: Here, we examined the molecular and cellular consequences of a 6 base-pair deletion of amino acids Glu(287) and Ser(288) (∆ES) in the predicted seventh transmembrane helix of human NHE6 expressed in established cell lines (CHO/AP-1, HeLa and neuroblastoma SH-SY5Y) and primary cultures of mouse hippocampal neurons by measuring levels of protein expression, stability, membrane trafficking, endosomal function and cell viability...
2016: Molecular Neurodegeneration
Meeta Cardon, Karen D Evankovich, J Lloyd Holder
Genes encoding proteins critical for intracellular vesicular transport are an emerging area of importance for neurologists. In particular, proteins that create and maintain the correct compartmental pH, such as the endosomal Na(+)/H(+) exchangers (NHEs), have been implicated in a wide range of human diseases, including cardiovascular, inflammatory bowel, renal, and neurologic disorders, which demonstrates the critical cellular function of these proteins.(1-3) Two NHEs, NHE6 and NHE9, have been linked to neurologic disorders in children...
April 2016: Neurology. Genetics
Hanshu Zhao, Karen E Carney, Lindsay Falgoust, Jullie W Pan, Dandan Sun, Zhongling Zhang
Epilepsy is a common central nervous system (CNS) disease characterized by recurrent transient neurological events occurring due to abnormally excessive or synchronous neuronal activity in the brain. The CNS is affected by systemic acid-base disorders, and epileptic seizures are sensitive indicators of underlying imbalances in cellular pH regulation. Na(+)/H(+) exchangers (NHEs) are a family of membrane transporter proteins actively involved in regulating intracellular and organellar pH by extruding H(+) in exchange for Na(+) influx...
March 2016: Progress in Neurobiology
Eric M Morrow, Sofia B Lizarraga, Qing Ouyang
No abstract text is available yet for this article.
December 2015: International Journal of Developmental Neuroscience
Hari Prasad, Rajini Rao
Early intervention may be key to safe and effective therapies in patients with Alzheimer disease. Endosomal dysfunction is an early step in neurodegeneration. Endosomes are a major site of production of Aβ peptide from the processing of amyloid precursor protein (APP) by clipping enzymes (β- and γ-secretases). The β-secretase enzyme BACE1 requires acidic lumen pH for optimum function, and acid pH promotes Aβ aggregation. The Na(+)/H(+) exchanger NHE6 provides a leak pathway for protons, limiting luminal acidification by proton pumps...
February 27, 2015: Journal of Biological Chemistry
Matthew F Pescosolido, David M Stein, Michael Schmidt, Christelle Moufawad El Achkar, Mark Sabbagh, Jeffrey M Rogg, Umadevi Tantravahi, Rebecca L McLean, Judy S Liu, Annapurna Poduri, Eric M Morrow
OBJECTIVE: Recently, Christianson syndrome (CS) has been determined to be caused by mutations in the X-linked Na(+) /H(+) exchanger 6 (NHE6). We aimed to determine the diagnostic criteria and mutational spectrum for CS. METHODS: Twelve independent pedigrees (14 boys, age = 4-19 years) with mutations in NHE6 were administered standardized research assessments, and mutations were characterized. RESULTS: The mutational spectrum was composed of 9 single nucleotide variants, 2 indels, and 1 copy number variation deletion...
October 2014: Annals of Neurology
Kalyan C Kondapalli, Hari Prasad, Rajini Rao
Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na(+)/H(+) exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na(+), K(+)) content in early and recycling endosomal compartments...
2014: Frontiers in Cellular Neuroscience
Nina Milosavljevic, Michaël Monet, Isabelle Léna, Frédéric Brau, Sandra Lacas-Gervais, Sylvain Feliciangeli, Laurent Counillon, Mallorie Poët
Vesicular H(+)-ATPases and ClC-chloride transporters are described to acidify intracellular compartments, which also express the highly conserved Na(+)/H(+) exchangers NHE6, NHE7, and NHE9. Mutations of these exchangers cause autism-spectrum disorders and neurodegeneration. NHE6, NHE7, and NHE9 are hypothesized to exchange cytosolic K(+) for H(+) and alkalinize vesicles, but this notion has remained untested in K(+) because their intracellular localization prevents functional measurements. Using proton-killing techniques, we selected a cell line that expresses wild-type NHE7 at the plasma membrane, enabling measurement of the exchanger's transport parameters...
May 8, 2014: Cell Reports
Ginevra Zanni, Sabina Barresi, Roni Cohen, Nicola Specchio, Lina Basel-Vanagaite, Enza Maria Valente, Avinoam Shuper, Federico Vigevano, Enrico Bertini
Mutations in the solute carrier family 9, subfamily A member 6 (SLC9A6) gene, encoding the endosomal Na+/H+ exchanger 6 (NHE6) are associated with Christianson syndrome, a syndromic form of X-linked intellectual disability characterized by microcephaly, severe global developmental delay, autistic behavior, early onset seizures and ataxia. In a 7-year-old boy with characteristic clinical and neuroimaging features of Christianson syndrome and epileptic encephalopathy with continuous spikes and waves during sleep, we identified a novel splice site mutation (IVS10-1G>A) in SLC9A6...
May 2014: Epilepsy Research
Daniel G Fuster, R Todd Alexander
The SLC9 gene family encodes Na(+)/H(+) exchangers (NHEs). These transmembrane proteins transport ions across lipid bilayers in a diverse array of species from prokaryotes to eukaryotes, including plants, fungi, and animals. They utilize the electrochemical gradient of one ion to transport another ion against its electrochemical gradient. Currently, 13 evolutionarily conserved NHE isoforms are known in mammals [22, 46, 128]. The SLC9 gene family (solute carrier classification of transporters: www.bioparadigms...
January 2014: Pflügers Archiv: European Journal of Physiology
Chan Choo Yap, Bettina Winckler
The sodium-proton exchanger NHE6 contributes to proper endosomal acidification. NHE6 mutations are also linked to autism-related disorders. In this issue of Neuron, using NHE6-knockout mice, Ouyang et al. (2013) uncover how dysregulation of endosomal pH leads to disturbances in BDNF signaling and neuronal morphogenesis defects.
October 2, 2013: Neuron
Alina Ilie, Erica Weinstein, Annie Boucher, R Anne McKinney, John Orlowski
Na(+)/H(+) exchanger NHE6/SLC9A6 is an X-linked gene that is widely expressed and especially abundant in brain, heart and skeletal muscle where it is implicated in endosomal pH homeostasis and trafficking as well as maintenance of cell polarity. Recent genetic studies have identified several mutations in the coding region of NHE6 that are linked with severe intellectual disability, autistic behavior, ataxia and other abnormalities. One such defect consists of an in-frame deletion of three amino acids ((370)Trp-Ser-Thr(372), ΔWST) that adjoin the predicted ninth transmembrane helix of the exchanger...
July 2014: Neurochemistry International
Qing Ouyang, Sofia B Lizarraga, Michael Schmidt, Unikora Yang, Jingyi Gong, Debra Ellisor, Julie A Kauer, Eric M Morrow
Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Na⁺/H⁺ exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength...
October 2, 2013: Neuron
M Schwede, K Garbett, K Mirnics, D H Geschwind, E M Morrow
No abstract text is available yet for this article.
March 2014: Molecular Psychiatry
Emily C Deane, Alina E Ilie, Saman Sizdahkhani, Micaela Das Gupta, John Orlowski, R Anne McKinney
Postsynaptic endosomal trafficking has emerged as a principal regulatory mechanism of structural and functional plasticity of glutamatergic synapses. Recycling endosomes perform activity-dependent transport of AMPA receptors (AMPARs) and lipids to the postsynaptic membrane, activities that are known to contribute to long-term synaptic potentiation and hypothesized to subserve learning and memory processes in the brain. Recently, genetic defects in a widely expressed vesicular pH-regulating transporter, the Na(+)/H(+) exchanger NHE6 isoform, have been implicated in neurodevelopmental disorders including severe X-linked mental retardation and autism...
January 9, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Matthew J Prior, Mark Larance, Robert T Lawrence, Jamie Soul, Sean Humphrey, James Burchfield, Carol Kistler, Jonathon R Davey, Penelope J La-Borde, Michael Buckley, Hiroshi Kanazawa, Robert G Parton, Michael Guilhaus, David E James
The adipocyte is a key regulator of mammalian metabolism. To advance our understanding of this important cell, we have used quantitative proteomics to define the protein composition of the adipocyte plasma membrane (PM) in the presence and absence of insulin. Using this approach, we have identified a high confidence list of 486 PM proteins, 52 of which potentially represent novel cell surface proteins, including a member of the adiponectin receptor family and an unusually high number of hydrolases with no known function...
November 4, 2011: Journal of Proteome Research
Lou Xinhan, Masafumi Matsushita, Manami Numaza, Akira Taguchi, Keiji Mitsui, Hiroshi Kanazawa
In mammalian cells, nine conserved isoforms of the Na(+)/H(+) exchanger (NHE) are known to be important for pH regulation of the cytoplasm and organellar lumens. NHE1-5 are localized to the plasma membrane, whereas NHE6-9 are localized to distinct organelles. NHE6 is localized predominantly in endosomal compartments but is also found in the plasma membrane. To investigate the role of NHE6 in endocytosis, we established NHE6-knockdown HeLa cells and analyzed the effect of this knockdown on endocytotic events...
December 2011: American Journal of Physiology. Cell Physiology
Yumi Takahashi, Kana Hosoki, Masafumi Matsushita, Makoto Funatsuka, Kayoko Saito, Hiroshi Kanazawa, Yu-Ichi Goto, Shinji Saitoh
SLC9A6 mutations have been reported in families in whom X-linked mental retardation (XMR) mimics Angelman syndrome (AS). However, the relative importance of SLC9A6 mutations in patients with an AS-like phenotype or XMR has not been fully investigated. Here, the involvement of SLC9A6 mutations in 22 males initially suspected to have AS but found on genetic testing not to have AS (AS-like cohort), and 104 male patients with XMR (XMR cohort), was investigated. A novel SLC9A6 mutation (c.441delG, p.S147fs) was identified in one patient in the AS-like cohort, but no mutation was identified in XMR cohort, suggesting mutations in SLC9A6 are not a major cause of the AS-like phenotype or XMR...
December 2011: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Li Liu, Paul H Schlesinger, Nicole M Slack, Peter A Friedman, Harry C Blair
Osteoblasts synthesize bone in polarized groups of cells sealed by tight junctions. Large amounts of acid are produced as bone mineral is precipitated. We addressed the mechanism by which cells manage this acid load by measuring intracellular pH (pHi) in non-transformed osteoblasts in response to weak acid or bicarbonate loading. Basal pHi in mineralizing osteoblasts was ∼ 7.3 and decreased by ∼ 1.4 units upon replacing extracellular Na(+) with N-methyl-D-glucamine. Loading with 40 mM acetic or propionic acids, in normal extracellular Na(+), caused only mild cytosolic acidification...
June 2011: Journal of Cellular Physiology
Richard J Schroer, Kenton R Holden, Patrick S Tarpey, Maria Giselle Matheus, David A Griesemer, Michael J Friez, Jane Zheng Fan, Richard J Simensen, Petter Strømme, Roger E Stevenson, Michael R Stratton, Charles E Schwartz
Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others. They also noted the clinical similarities to Angelman syndrome and found cerebellar atrophy on MRI and elevated glutamate/glutamine in the basal ganglia on MRS...
November 2010: American Journal of Medical Genetics. Part A
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