scholarly journals Unusual Clinical Presentation and Possible Rescue of a Novel Claudin-16 Mutation

2006 ◽  
Vol 91 (8) ◽  
pp. 3076-3079 ◽  
Author(s):  
Dominik Müller ◽  
P. Jaya Kausalya ◽  
Detlef Bockenhauer ◽  
Julia Thumfart ◽  
Iwan C. Meij ◽  
...  
Keyword(s):  
Mdck Cells ◽  
Novel Mutation ◽  
Surface Expression ◽  
Blood Analysis ◽  
Mutant Protein ◽  
Molecular Defects ◽  
Familial Hypomagnesemia ◽  
Novel Therapeutic Strategies ◽  
Urine And Serum

Abstract Context: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is caused by a dysfunction of Claudin-16 (CLDN16) and characterized by renal wasting of Mg2+ and Ca2+. Objective: The objectives of this study were to study the clinical parameters in suspected FHHNC patients, identify mutations in the CLDN16 gene, and analyze molecular defects associated with the mutant protein. Design, Setting, and Participants: CLDN16 genes from two siblings diagnosed with FHHNC were sequenced. Expression and characterization of the mutant protein in renal MDCK cells were studied. Outcome Measures: Standard urine and serum parameters to diagnose FHHNC were determined. Mutations in the CLDN16 gene were identified. The subcellular distribution of the mutant protein was analyzed by immunofluorescence microscopy. Results: Urine and blood analysis showed signs typical for FHHNC. One patient, in addition, presented with hypocalcemic tetany, a phenomenon so far not described for FHHNC. Both siblings carry a novel mutation in CLDN16, Y207X. The review of medical records showed that hypocalcemia is not uncommon in the early childhood of FHHNC patients. Expressed in MDCK cells, the Y207X mutant is not detected at tight junctions but instead is found in lysosomes and, to a lesser extent, the endoplasmic reticulum. Surface expression can be rescued by inhibiting clathrin-mediated internalization. Conclusions: We propose that mutations in CLDN16 are considered in childhood hypocalcemia. CLDN16 Y207X is transiently delivered to the plasma membrane but not retained and is rapidly retrieved by internalization. Inhibitors of endocytosis may provide novel therapeutic strategies.

Characterization of a mutant R11H αB-crystallin associated with human inherited cataract

2010 ◽  
Vol 391 (12) ◽  
Author(s):  
Qiang Chen ◽  
Ming Yan ◽  
Feiyan Xiang ◽  
Xin Zhou ◽  
Yuanyuan Liu ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Surface Hydrophobicity ◽  
Mutant Protein ◽  
Wild Type ◽  
Type Form ◽  
Αb Crystallin ◽  
Cataract Development ◽  
Wild Type Form ◽  
Hydrophobic Exposure

Abstract αB-Crystallin plays an important part in cataract development. A novel mutation (R11H) was previously detected by our group. In the present study, we set out to investigate the possible molecular mechanism by which the R11H mutation causes cataract. We found that the mutant αB-crystallin exhibits folding defects, decreased surface hydrophobicity and enhanced chaperone-like activity compared with the wild-type αB-crystallin. The mutant protein shows nearly the same molecular mass and thermal stability as the wild-type form. Transfection studies revealed that the R11H mutant was remarkably similar to the wild-type protein in its subcellular distribution, but has an abnormal ability to induce cell apoptosis. These results suggest that the changes in hydrophobic exposure and the abnormal ability to induce programmed cell death of the mutant protein are likely to be responsible for the onset of cataract.

scholarly journals Identification and characterization of a novel ABCA3 mutation

2010 ◽  
Vol 40 (2) ◽  
pp. 94-99 ◽  
Author(s):  
Sang-Kyu Park ◽  
Louella Amos ◽  
Aparna Rao ◽  
Michael W. Quasney ◽  
Yoshihiro Matsumura ◽  
...  
Keyword(s):  
Premature Infant ◽  
Respiratory Insufficiency ◽  
Atp Hydrolysis ◽  
Novel Mutation ◽  
Intracellular Localization ◽  
Hek293 Cells ◽  
Mutant Protein ◽  
Chronic Respiratory Insufficiency ◽  
Hydrolysis Activity

Mutations in the gene coding for ATP-binding cassette protein A3 (ABCA3) are recognized as a genetic cause of lung disease of varying severity. Characterization of a number of mutant ABCA3 proteins has demonstrated that the mutations generally affect intracellular localization or the ability of the protein to hydrolyze ATP. A novel heterozygous mutation that results in the substitution of cysteine for arginine at amino acid 295 in ABCA3 was identified in a premature infant with chronic respiratory insufficiency and abnormal lamellar bodies. Sequencing of DNA performed in study participants demonstrated that this was a mutation and not a common variant. Plasmid vectors containing ABCA3 with the identified novel mutation tagged with green fluorescent protein on the carboxy terminus were generated. The effect of the mutation on protein function was characterized by examining the glycosylation state of the mutant protein in transiently transfected HEK293 cells and by examining ATP hydrolysis activity of the mutant protein with a vanadate-induced nucleotide trapping assay in stably transfected HEK293 cells. The ABCA3 protein containing the R295C mutation undergoes normal glycosylation and intracellular localization but has dramatically reduced ATP hydrolysis activity (12% of wild type). The identification of one copy of this novel mutation in a premature infant with chronic respiratory insufficiency suggests that ABCA3 haploinsufficiency together with lung prematurity may result in more severe, or more prolonged, respiratory failure.

Characterization of the Original Christmas Disease Mutation (Cysteine 206 → Serine): From Clinical Recognition to Molecular Pathogenesis

1992 ◽  
Vol 67 (01) ◽  
pp. 063-065 ◽  
Author(s):  
Sherryl A M Taylor ◽  
Jacalyn Duffin ◽  
Cherie Cameron ◽  
Jerome Teitel ◽  
Bernadette Garvey ◽  
...  
Keyword(s):  
Nucleotide Substitution ◽  
Novel Mutation ◽  
Factor Ix ◽  
Causative Mutation ◽  
Coding Region ◽  
Body Of Knowledge ◽  
Polymerase Chain ◽  
Splice Junctions

SummaryChristmas disease was first reported as a distinct clinical entity in two manuscripts published in 1952 (1, 2). The eponym associated with this disorder, is the surname of the first patient examined in detail and reported by Biggs and colleagues in a paper describing the clinical and laboratory features of seven affected individuals (3). This patient has severe factor IX coagulant deficiency (less than 0.01 units/ml) and no detectable circulating factor IX antigen (less than 0.01 units/ml). Coding sequence and splice junctions of the factor IX gene from this patient have been amplified in vitro through the polymerase chain reaction (PCR). One nucleotide substitution was identified at nucleotide 30,070 where a guanine was replaced by a cytosine. This mutation alters the amino acid encoded at position 206 in the factor IX protein from cysteine to serine. The non conservative nature of this substitution, the absence of this change in more than 200 previously sequenced factor IX genes and the fact that the remainder of the coding region of this gene was normal, all provide strong circumstantial evidence in favour of this change being the causative mutation in this patient. The molecular characterization of this novel mutation in the index case of Christmas disease, contributes to the rapidly expanding body of knowledge pertaining to Christmas disease pathogenesis.

scholarly journals Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 105 ◽  
Author(s):  
Maria Zella ◽  
Judith Metzdorf ◽  
Friederike Ostendorf ◽  
Fabian Maass ◽  
Siegfried Muhlack ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glial Cell ◽  
Dopaminergic Neurons ◽  
Basic Research ◽  
Alpha Synuclein ◽  
Models Of Disease ◽  
Novel Therapeutic Strategies ◽  
Lymphocyte Populations

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

Molecular Characterization of a Novel Mutation in APRT Heterozygotes

1995 ◽  
pp. 675-678 ◽  
Author(s):  
Amrik Sahota ◽  
Steve Bye ◽  
Ju Chen ◽  
Nada H. Khattar ◽  
Mitchell S. Turker ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Novel Mutation

scholarly journals Identification and Characterization of a Novel Mutation M579Fs+75X in HERG

2011 ◽  
Vol 27 (Supplement) ◽  
pp. PJ3_045
Author(s):  
Yukiko Hata ◽  
Hisashi Mori ◽  
Ayumi Tanaka ◽  
Yosuke Fujita ◽  
Takeshi Shimomura ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Identification And Characterization

scholarly journals GP96 drives exacerbation of secondary bacterial pneumonia following influenza A virus infection

2020 ◽  
Author(s):  
Tomoko Sumitomo ◽  
Masanobu Nakata ◽  
Satoshi Nagase ◽  
Yuki Takahara ◽  
Mariko Honda-Ogawa ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Influenza A Virus ◽  
Transcriptional Repression ◽  
Bacterial Pneumonia ◽  
Influenza A ◽  
Surface Expression ◽  
Lung Pathology ◽  
Direct Binding ◽  
Novel Therapeutic Strategies ◽  
Secondary Bacterial Pneumonia

AbstractInfluenza A virus (IAV) infection predisposes the host to secondary bacterial pneumonia, known as a major cause of morbidity and mortality during influenza epidemics. Analysis of interactions between IAV-infected human epithelial cells and Streptococcus pneumoniae revealed that infected cells ectopically exhibited the endoplasmic reticulum chaperon GP96 on the surface. Importantly, efficient pneumococcal adherence to epithelial cells was imparted by interactions with extracellular GP96 and integrin αV, with the surface expression mediated by GP96 chaperone activity. Furthermore, abrogation of adherence was gained by chemical inhibition or genetic knockout of GP96, as well as addition of RGD peptide. Direct binding of extracellular GP96 and pneumococci was shown to be mediated by pneumococcal oligopeptide permease components. Additionally, IAV infection induced activation of calpains and Snail1, which are responsible for degradation and transcriptional repression of junctional proteins in the host, respectively, indicating increased bacterial translocation across the epithelial barrier. Notably, treatment of IAV-infected mice with the GP96 inhibitor enhanced pneumococcal clearance from lung tissues and ameliorated lung pathology. Taken together, the present findings indicate a viral-bacterial synergy in relation to disease progression and suggest a paradigm for developing novel therapeutic strategies tailored to inhibit pneumococcal colonization in an IAV-infected respiratory tract.

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