scholarly journals Molecular Characterization of CNTS Mutations in Tunisian Patients with Ocular Cystinosis

2021 ◽  
Author(s):  
latifa chkioua ◽  
Yessine Amri ◽  
Chayma Saheli ◽  
Wassila Mili ◽  
Sameh Mabrouk ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Membrane Lipids ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Phospholipid Bilayer ◽  
Crystallographic Structure ◽  
Department Of Ophthalmology ◽  
Tunisian Patients

Abstract Background: Ocular cystinosis is a rare autosomal recessive disorder characterized by intralysosomal cystine accumulation in renal, ophthalmic (cornea, conjunctiva), and other organ abnormalities. Patients with ocular cystinosis are mostly asymptomatic and typically experience mild photophobia due to cystine crystals in the cornea observed accidently during a routine ocular examination. The ocular cystinosis is associated with different mutations in CTNS gene. Cysteamine therapy mostly corrects the organ abnormalities. Methods: This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital. The Optical Coherence Tomography (OCT) of the cornea and retinal photography were used to search cystine crystals within the corneas and conjunctiva in eight Tunisian patients. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene. Results: The studied patients were found to have cystine crystal limited anterior corneal stroma and the conjunctiva associated with retinal crystals accumulation. CTNS gene sequencing disclosed 7 mutations: three missense mutations (G308R, p.Q88K, and p.S139Y); one duplication (C.829dup), one framshift mutation (p.G258f), one splice site mutation (c.681+7delC) and a large deletion (20327-bp deletion). Crystallographic structure analysis suggests that the novel mutation p.S139Y is buried in a first transmembrane helix closed to the lipid bilayer polar region, introducing a difference in hydrophobicity which could affect the hydrophobic interactions with the membrane lipids. The second novel mutation p.Q88K which is located in the lysosomal lumen close to the lipid membrane polar head region, introduced a basic amino acid in a region which tolerate only uncharged residue. The third missense mutation introduces a positive change in nonpolar tail region of the phospholipid bilayer membrane affecting the folding and stability of the protein in the lipid bilayer. Conclusion: Our data demonstrate that impaired transport of cystine out of lysosomes is the most common, which is obviously associated with the mutations of transmembrane domains of cystinosine resulting from a total loss of its activity.

scholarly journals Ophthalmic and Genetics Profiles of Cystinosis in Tunisian Patients

2021 ◽  
Author(s):  
Latifa Chkioua ◽  
Yessine Amri ◽  
Chayma Saheli ◽  
Wassila Mili ◽  
Sameh Mabrouk ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Membrane Lipids ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Phospholipid Bilayer ◽  
Crystallographic Structure ◽  
Department Of Ophthalmology ◽  
Tunisian Patients

Abstract Background: Ocular cystinosis is a rare autosomal recessive disorder characterized by intralysosomal cystine accumulation in renal, ophthalmic (cornea, conjunctiva), and other organ abnormalities. Patients with ocular cystinosis are mostly asymptomatic and typically experience mild photophobia due to cystine crystals in the cornea observed accidently during a routine ocular examination. The ocular cystinosis is associated with different mutations in CTNS gene. Cysteamine therapy mostly corrects the organ abnormalities. Methods: This study was performed in collaboration with the department of ophthalmology of Farhat Hached Hospital. The Optical Coherence Tomography (OCT) of the cornea and retinal photography were used to search cystine crystals within the corneas and conjunctiva in eight Tunisian patients. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the entire CTNS gene. Results: The studied patients were found to have cystine crystal limited anterior corneal stroma and the conjunctiva associated with retinal crystals accumulation. CTNS gene sequencing disclosed 7 mutations: three missense mutations (G308R, p.Q88K, and p.S139Y); one duplication (C.829dup), one framshift mutation (p.G258f), one splice site mutation (c.681+7delC) and a large deletion (20327-bp deletion). Crystallographic structure analysis suggests that the novel mutation p.S139Y is buried in a first transmembrane helix closed to the lipid bilayer polar region, introducing a difference in hydrophobicity which could affect the hydrophobic interactions with the membrane lipids. The second novel mutation p.Q88K which is located in the lysosomal lumen close to the lipid membrane polar head region, introduced a basic amino acid in a region which tolerate only uncharged residue. The third missense mutation introduces a positive change in nonpolar tail region of the phospholipid bilayer membrane affecting the folding and stability of the protein in the lipid bilayer. Conclusion: Our data demonstrate that impaired transport of cystine out of lysosomes is the most common, which is obviously associated with the mutations of transmembrane domains of cystinosine resulting from a total loss of its activity.

scholarly journals Discrete Conductance Fluctuations in Lipid Bilayer Protein Membranes

1969 ◽  
Vol 53 (6) ◽  
pp. 741-757 ◽  
Author(s):  
R. C. Bean ◽  
W. C. Shepherd ◽  
H. Chan ◽  
Joellen Eichner
Keyword(s):  
Lipid Bilayer ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Membrane Lipids ◽  
Initial Reaction ◽  
Lipid Bilayer Membranes ◽  
Conductance Fluctuations ◽  
Excitable Membranes ◽  
Conductance States ◽  
High Conductance

Discrete fluctuations in conductance of lipid bilayer membranes may be observed during the initial stages of membrane interaction with EIM ("excitability inducing material"), during destruction of the EIM conductance by proteolysis, and during the potential-dependent transitions between low and high conductance states in the "excitable" membranes. The discrete conductance steps observed during the initial reaction of EIM with the lipid membranes are remarkably uniform, even in membranes of widely varying lipid composition. They range only from 2 to 6 x 10-10 ohm-1 and average 4 x 10-10 ohm-1. Steps found during destruction of the EIM conductance by proteolysis are somewhat smaller. The transition between high conductance and low conductance states may involve steps as small as 0.5 x 10-10 ohm-1. These phenomena are consistent with the formation of a stable protein bridge across the lipid membrane to provide a polar channel for the transport of cations. T6he uniform conductance fluctuations observed during the formation of these macromolecular channels may indicate that the ions in a conductive channel, in its open state, are largely protected from the influence of the polar groups of the membrane lipids. Potential-dependent changes in conductance may be due to configurational or positional changes in the protein channel. Differences in lipid-lipid and lipid-macromolecule interactions may account for the variations in switching kinetics in various membrane systems.

scholarly journals Lipid bilayer degradation induced by SARS-CoV-2 spike protein as revealed by neutron reflectometry

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alessandra Luchini ◽  
Samantha Micciulla ◽  
Giacomo Corucci ◽  
Krishna Chaithanya Batchu ◽  
Andreas Santamaria ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Membrane Lipids ◽  
Lipid Extraction ◽  
Specific Interaction ◽  
Structural Features ◽  
Supported Lipid Bilayers ◽  
Fusion Event ◽  
Angiotensin Converting Enzyme 2 ◽  
Neutron Reflection

AbstractSARS-CoV-2 spike proteins are responsible for the membrane fusion event, which allows the virus to enter the host cell and cause infection. This process starts with the binding of the spike extramembrane domain to the angiotensin-converting enzyme 2 (ACE2), a membrane receptor highly abundant in the lungs. In this study, the extramembrane domain of SARS-CoV-2 Spike (sSpike) was injected on model membranes formed by supported lipid bilayers in presence and absence of the soluble part of receptor ACE2 (sACE2), and the structural features were studied at sub-nanometer level by neutron reflection. In all cases the presence of the protein produced a remarkable degradation of the lipid bilayer. Indeed, both for membranes from synthetic and natural lipids, a significant reduction of the surface coverage was observed. Quartz crystal microbalance measurements showed that lipid extraction starts immediately after sSpike protein injection. All measurements indicate that the presence of proteins induces the removal of membrane lipids, both in the presence and in the absence of ACE2, suggesting that sSpike molecules strongly associate with lipids, and strip them away from the bilayer, via a non-specific interaction. A cooperative effect of sACE2 and sSpike on lipid extraction was also observed.

scholarly journals The Impact of O-Glycosylation on Cyanidin Interaction with POPC Membranes: Structure-Activity Relationship

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2771
Author(s):  
Sylwia Cyboran-Mikołajczyk ◽  
Piotr Jurkiewicz ◽  
Martin Hof ◽  
Halina Kleszczyńska
Keyword(s):  
Biological Activity ◽  
Free Radicals ◽  
Lipid Bilayer ◽  
Lipid Membrane ◽  
Lipid Vesicles ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Beneficial Effects ◽  
Structure Activity ◽  
The Impact

Cyanidin and its O-glycosides have many important physiological functions in plants and beneficial effects on human health. Their biological activity is not entirely clear and depends on the structure of the molecule, in particular, on the number and type of sugar substituents. Therefore, in this study the detailed structure-activity relationship (SARs) of the anthocyanins/anthocyanidins in relation to their interactions with lipid bilayer was determined. On the basis of their antioxidant activity and the changes induced by them in size and Zeta potential of lipid vesicles, and mobility and order of lipid acyl chains, the impact of the number and type of sugar substituents on the biological activity of the compounds was evaluated. The obtained results have shown, that 3-O-glycosylation changes the interaction of cyanidin with lipid bilayer entirely. The 3-O-glycosides containing a monosaccharide induces greater changes in physical properties of the lipid membrane than those containing disaccharides. The presence of additional sugar significantly reduces glycoside interaction with model lipid membrane. Furthermore, O-glycosylation alters the ability of cyanidin to scavenge free radicals. This alteration depends on the type of free radicals and the sensitivity of the method used for their determination.

scholarly journals The interplay between lipids and dopamine on α-synuclein oligomerization and membrane binding

2013 ◽  
Vol 33 (5) ◽  
Author(s):  
Chi L. L. Pham ◽  
Roberto Cappai
Keyword(s):  
Lipid Membranes ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Membrane Integrity ◽  
Lipid Vesicles ◽  
Helical Conformation ◽  
Unfolded Protein ◽  
Natively Unfolded Protein ◽  
Natively Unfolded

The deposition of α-syn (α-synuclein) as amyloid fibrils and the selective loss of DA (dopamine) containing neurons in the substantia nigra are two key features of PD (Parkinson's disease). α-syn is a natively unfolded protein and adopts an α-helical conformation upon binding to lipid membrane. Oligomeric species of α-syn have been proposed to be the pathogenic species associated with PD because they can bind lipid membranes and disrupt membrane integrity. DA is readily oxidized to generate reactive intermediates and ROS (reactive oxygen species) and in the presence of DA, α-syn form of SDS-resistant soluble oligomers. It is postulated that the formation of the α-syn:DA oligomers involves the cross-linking of DA-melanin with α-syn, via covalent linkage, hydrogen and hydrophobic interactions. We investigate the effect of lipids on DA-induced α-syn oligomerization and studied the ability of α-syn:DA oligomers to interact with lipids vesicles. Our results show that the interaction of α-syn with lipids inhibits the formation of DA-induced α-syn oligomers. Moreover, the α-syn:DA oligomer cannot interact with lipid vesicles or cause membrane permeability. Thus, the formation of α-syn:DA oligomers may alter the actions of α-syn which require membrane association, leading to disruption of its normal cellular function.

scholarly journals Fusion of phospholipid vesicles with a planar membrane depends on the membrane permeability of the solute used to create the osmotic pressure.

1989 ◽  
Vol 93 (2) ◽  
pp. 201-210 ◽  
Author(s):  
F S Cohen ◽  
W D Niles ◽  
M H Akabas
Keyword(s):  
Osmotic Pressure ◽  
Lipid Bilayer ◽  
Lipid Membrane ◽  
Contact Region ◽  
Companion Paper ◽  
Phospholipid Vesicles ◽  
Osmotic Gradient ◽  
Vesicle Membrane ◽  
Permeable Channel ◽  
Planar Membrane

Phospholipid vesicles fuse with a planar membrane when they are osmotically swollen. Channels in the vesicle membrane are required for swelling to occur when the vesicle-containing compartment is made hyperosmotic by adding a solute (termed an osmoticant). We have studied fusion using two different channels, porin, a highly permeable channel, and nystatin, a much less permeable channel. We report that an osmoticant's ability to support fusion (defined as the magnitude of osmotic gradient necessary to obtain sustained fusion) depends on both its permeability through lipid bilayer as well as its permeability through the channel by which it enters the vesicle interior. With porin as the channel, formamide requires an osmotic gradient about ten times that required with urea, which is approximately 1/40th as permeant as formamide through bare lipid membrane. When nystatin is the channel, however, fusion rates sustained by osmotic gradients of formamide are within a factor of two of those obtained with urea. Vesicles containing a porin-impermeant solute can be induced to swell and fuse with a planar membrane when the impermeant bathing the vesicles is replaced by an isosmotic quantity of a porin-permeant solute. With this method of swelling, formamide is as effective as urea in obtaining fusion. In addition, we report that binding of vesicles to the planar membrane does not make the contact region more permeable to the osmoticant than is bare lipid bilayer. In the companion paper, we quantitatively account for the observation that the ability of a solute to promote fusion depends on its permeability properties and the method of swelling. We show that the intravesicular pressure developed drives fusion.

Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review

2021 ◽  
Author(s):  
Yosra Bouyacoub ◽  
Cyrine Drissi ◽  
Ichraf Kraoua ◽  
Mariem Chargui ◽  
Ibtihel Rebai ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Congenital Cataract ◽  
Direct Sequencing ◽  
Autosomal Recessive Disorder ◽  
Resonance Imaging ◽  
Neurologic Impairment ◽  
Tunisian Patients ◽  
Myelin Deficiency ◽  
The Brain ◽  
Genotype Correlation

AbstractHypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype–genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.

Selective arrangement of vesicles on artificial lipid membrane by biotin-avidin interaction

2021 ◽  
Author(s):  
Kai Hashino ◽  
Daiya Mombayashi ◽  
Yuto Nakatani ◽  
Azusa Oshima ◽  
Masumi Yamaguchi ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Lipid Bilayers ◽  
Liquid Crystalline ◽  
Lipid Membrane ◽  
Unsaturated Lipid ◽  
Si Substrates ◽  
Phase Domain ◽  
Unsaturated Lipids ◽  
Lipid Mixtures ◽  
The Difference

Abstract Lipid bilayers suspended over microwells on Si substrates are promising platforms for nanobiodevices that mimic cell membranes. Using the biotin-avidin interaction, we have succeeded in selectively arranging vesicles on the freestanding region of a lipid bilayer. When ternary lipid mixtures of saturated lipid, unsaturated lipid, and cholesterol are used, they separate into liquid-order (Lo) and liquid-crystalline (Lα) domains. A freestanding lipid bilayer prefers the Lα-phase over the Lo-phase because of the difference in their flexibility. In addition, the type of biotinylated lipid determines whether it is localized in the Lα-phase domain or the Lo-phase domain. As a result, the biotinylated unsaturated lipids localized in the Lα-phase domain aggregate in the freestanding lipid bilayer, and vesicles labeled with biotin selectively bind to the freestanding lipid bilayer by the biotin-avidin interaction. This technique helps to introduce biomolecules into the freestanding lipid bilayer of nanobiodevices via vesicles.

scholarly journals Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family

2008 ◽  
Vol 52 (8) ◽  
pp. 1272-1276 ◽  
Author(s):  
Maria Edna de Melo ◽  
Suemi Marui ◽  
Vinícius Nahime de Brito ◽  
Marcio Corrêa Mancini ◽  
Berenice B. Mendonca ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Arginine Vasopressin ◽  
Autosomal Dominant ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Sequencing Analysis ◽  
The Novel ◽  
Autosomal Dominant Disorder ◽  
Vasopressin Gene ◽  
Avp Gene

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

scholarly journals Computational Study of the Interaction of a PEGylated Hyperbranched Polymer/Doxorubicin Complex with a Bilipid Membrane

Fluids ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 17 ◽  
Author(s):  
Prodromos Arsenidis ◽  
Kostas Karatasos
Keyword(s):  
Hyperbranched Polymer ◽  
Lipid Membrane ◽  
Hydrophobic Interactions ◽  
Computational Study ◽  
Translational Motion ◽  
Spatial Arrangement ◽  
Aqueous Environment ◽  
Drug Molecules ◽  
Dynamics Simulations ◽  
A Charge

Fully atomistic molecular dynamics simulations are employed to study in detail the interactions between a complex comprised by a PEGylated hyperbranched polyester (HBP) and doxorubicin molecules, with a model dipalmitoylphosphatidylglycerol membrane in an aqueous environment. The effects of the presence of the lipid membrane in the drug molecules’ spatial arrangement were examined in detail and the nature of their interaction with the latter were discussed and quantified where possible. It was found that a partial migration of the drug molecules towards the membrane’s surface takes place, driven either by hydrogen-bonding (for the protonated drugs) or by hydrophobic interactions (for the neutral drug molecules). The clustering behavior of the drug molecules appeared to be enhanced in the presence of the membrane, while the development of a charge excess close to the surface of the hyperbranched polymer and of the lipid membrane was observed. The uneven charge distribution created an effective overcharging of the HBP/drug complex and the membrane/drug surface. The translational motion of the drug molecules was found to be strongly affected by the presence of the membrane. The extent of the observed changes depended on the charge of the drug molecule. The build-up of the observed charge excesses close to the surface of the polymeric host and the membrane, together with the changes in the diffusional behavior of the drug molecules are of particular interest. Both phenomena could be important at the latest stages of the liposomal disruption and the release of the drug cargo in formulations based on relevant liposomal carriers.

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