7 research outputs found
Prediction of conformational changes by single mutation in the hepatitis B virus surface antigen (HBsAg) identified in HBsAg-negative blood donors
<p>Abstract</p> <p>Background</p> <p>Selection of hepatitis B virus (HBV) by host immunity has been suggested to give rise to variants with amino acid substitutions at or around the <it>'a' </it>determinant of the surface antigen (HBsAg), the main target of antibody neutralization and diagnostic assays. However, there have never been successful attempts to provide evidence for this hypothesis, partly because the 3 D structure of HBsAg molecules has not been determined. Tertiary structure prediction of HBsAg solely from its primary amino acid sequence may reveal the molecular energetic of the mutated proteins. We carried out this preliminary study to analyze the predicted HBsAg conformation changes of HBV variants isolated from Indonesian blood donors undetectable by HBsAg assays and its significance, compared to other previously-reported variants that were associated with diagnostic failure.</p> <p>Results</p> <p>Three HBV variants (T123A, M133L and T143M) and a wild type sequence were analyzed together with frequently emerged variants T123N, M133I, M133T, M133V, and T143L. Based on the Jameson-Wolf algorithm for calculating antigenic index, the first two amino acid substitutions resulted in slight changes in the antigenicity of the <it>'a' </it>determinant, while all four of the comparative variants showed relatively more significant changes. In the pattern T143M, changes in antigenic index were more significant, both in its coverage and magnitude, even when compared to variant T143L. These data were also partially supported by the tertiary structure prediction, in which the pattern T143M showed larger shift in the HBsAg second loop structure compared to the others.</p> <p>Conclusions</p> <p>Single amino acid substitutions within or near the <it>'a' </it>determinant of HBsAg may alter antigenicity properties of variant HBsAg, which can be shown by both its antigenic index and predicted 3 D conformation. Findings in this study emphasize the significance of variant T143M, the prevalent isolate with highest degree of antigenicity changes found in Indonesian blood donors. This highlights the importance of evaluating the effects of protein structure alterations on the sensitivity of screening methods being used in detection of ongoing HBV infection, as well as the use of vaccines and immunoglobulin therapy in contributing to the selection of HBV variants.</p
Reverse-Transcriptase Characteristics of Hepatitis B Virus Polymerase Gene in Treatment-Naïve Asymptomatic Chronic Hepatitis B Individuals
Nucleos(t)ide analogues (NUCs) remain the main treatment for chronic hepatitis B (CHB). Long-term use of NUCs significantly reduces disease progression; however, it might lead to resistance-associated mutations. We studied characteristics of polymerase gene related to NUCs resistance in naïve hepatitis B surface antigen (HBsAg)-positive individuals. The research was done at Laboratory of Hepatitis, Eijkman Institute, Jakarta Thirty eight samples were obtained and submitted for HBV DNA detection. Identification of mutations was performed by PCR-sequencing, and analyzed to obtain NUCs resistance motifs. Genotype and subtype were determined based on HBsAg sequence. Mutation of rtQ238H/N was found in 37 (97.4%) samples. Of those, 23 (62.2%) showed rtQ238H mutation, 10 (27.0%) had rtQ238N mutation, and four (10.8%) with double mutations of rtA194T and rtQ238H. Genotype B was found in 26 (68.4%), C in 11 (28.9%), and D in one (2.6%) samples. Statistically, the mutation variant of rtQ238H was associated with genotype B (p<0.001), while rtQ238N with C (p<0.001). The ayw subtype was found in 25 (65.8%), adr in 11 (28.9%), and adw in two (5.3%) samples. No mutation associated with NUCs resistance was found in most samples. This emphasizes that NUCs are still a prospective treatment in naïve CHB patients. Mutation of rtQ238H was a variant found to be significantly associated with HBV genotype B and rtQ238N with genotype C
Ethnogeographical structure of hepatitis B virus genotype distribution in Indonesia and discovery of a new subgenotype, B9
Erratum to: Occult hepatitis B in blood donors in Indonesia: altered antigenicity of the hepatitis B virus surface protein
The familial dementia gene revisited: a missense mutation revealed by whole exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family
Audo, Isabelle et al.Inherited retinal diseases are a group of clinically and genetically heterogeneous disorders for which a significant number of cases remain genetically unresolved. Increasing knowledge on underlying pathogenic mechanisms with precise phenotype-genotype correlation is, however, critical for establishing novel therapeutic interventions for these yet incurable neurodegenerative conditions. We report phenotypic and genetic characterization of a large family presenting an unusual autosomal dominant retinal dystrophy. Phenotypic characterization revealed a retinopathy dominated by inner retinal dysfunction and ganglion cell abnormalities. Whole-exome sequencing identified a missense variant (c.782A>C, p.Glu261Ala) in ITM2B coding for Integral Membrane Protein 2B, which co-segregates with the disease in this large family and lies within the 24.6 Mb interval identified by microsatellite haplotyping. The physiological role of ITM2B remains unclear and has never been investigated in the retina. RNA in situ hybridization reveals Itm2b mRNA in inner nuclear and ganglion cell layers within the retina, with immunostaining demonstrating the presence of the corresponding protein in the same layers. Furthermore, ITM2B in the retina co-localizes with its known interacting partner in cerebral tissue, the amyloid ß precursor protein, critical in Alzheimer disease physiopathology. Interestingly, two distinct ITM2B mutations, both resulting in a longer protein product, had already been reported in two large autosomal dominant families with Alzheimer-like dementia but never in subjects with isolated retinal diseases. These findings should better define pathogenic mechanism(s) associated with ITM2B mutations underlying dementia or retinal disease and add a new candidate to the list of genes involved in inherited retinal dystrophies.The project was supported by GIS-maladies rares (C.Z.), Retina
France (part of the 100-Exome Project) (I.A., J.-A.S. and C.Z.),
Foundation Voir et Entendre (C.Z.), Foundation Fighting Blindness
(FFB) grant CD-CL-0808-0466-CHNO (I.A. and the
CIC503, recognized as an FFB centre), FFB grant
C-CMM-0907-0428-INSERM04, Ville de Paris and Region
Ile de France and by the French State programme ‘Investissements
d’Avenir’ managed by the Agence Nationale de la
Recherche (LIFESENSES: ANR-10-LABX-65)Peer Reviewe