Integrating Population Variants and Protein Structural Analysis to Improve Clinical Genetic Diagnosis and Treatment in Nephrogenic Diabetes Insipidus

Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. We utilized a multicenter strategy to investigate the genotype and phenotype in a cohort of Chinese children clinically diagnosed with NDI from 2014 to 2019. Ten boys from nine families were identified with mutations in AVPR2 or AQP2 along with dehydration, polyuria–polydipsia, and severe hypernatremia. Genetic screening confirmed the diagnosis of seven additional relatives with partial or subclinical NDI. Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane region of AVPR2 and an enrichment of diagnostic mutations in the C-terminal region of AQP2. The pathogenic variants are significantly more likely to be located inside the domain compared with population variants. Through the structural analysis and in silico prediction, the eight mutations identified in this study were presumed to be disease-causing. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment for hypernatremia dehydration in neonates should not use isotonic saline as a rehydration fluid. Genetic analysis presumably confirmed the diagnosis of NDI in each patient in our study. We outlined methods for the early identification of NDI through phenotype and genotype, and outlined optimized treatment strategies.

Effect of RBD mutation (Y453F) in spike glycoprotein of SARS-CoV-2 on neutralizing antibody affinity

Natural selection “adaptation” in the coronavirus can occur during coronavirus amplification in vivo in farmed minks. Natural selection in such viruses is observed by introduction of mutations in SARS- CoV-2 that are not observed during the growth process in humans. Infection with a mutant (Y453F) of SARS-CoV-2 from farmed minks is known to widely spread among humans. We investigated the virological characteristics of this SARS-CoV-2 mutant (Y453F) using three-dimensional protein structural analysis. Our experimental study suggests that virus variants with the Y453F mutation partially escaped detection by four neutralizing monoclonal antibodies. The spread of SARS-CoV-2 variants mediated by millions of infected farmed minks is uncontrolled; consequently, raising a concern that infection of SARS-CoV-2 mutants that cause serious symptoms in humans may spread globally.

Integrating population variation and protein structural analysis to improve the clinical genetic diagnosis and treatment in children with congenital nephrogenic diabetes insipidus

Background and Objectives: Congenital nephrogenic diabetes insipidus (NDI) is a rare genetic disorder characterized by renal inability to concentrate urine. Establishing the genetic diagnosis appears particularly important to NDI for early detection and differential diagnosis.Method: We utilized a Chinese multicenter registry to investigate genotype and phenotype in children with NDI from 2014 to 2019. The structural locations of the pathogenic mutations from this study and the literature, as well as population variants retried from gnomAD were analyzed. Results: A total of 10 boys from 9 families carried mutations in AVPR2 (8/10) or AQP2 (2/10). Another 7 relatives of the families were diagnosed by sequencing for partial or subclinical NDI. Patients presented with dehydration, polyuria-polydipsia, and severe hypernatremia with a median age at diagnosis of 1.0 month (IQR 0.16, 18). Protein structural analysis revealed a notable clustering of diagnostic mutations in the transmembrane regions of AVPR2, and enrichment of diagnostic mutations by autosomal dominant inheritance (AD) in the C terminal region of AQP2. The pathogenic mutations are significantly more likely to be buried inside the domain comparing the population variants. Through structural analysis and in silico prediction, the eight mutations identified in this study were considered as presumably disease causative. The most common treatments were thiazide diuretics and non-steroidal anti-inflammatory drugs (NSAIDs). Emergency treatment of hypernatremic dehydration in neonates should not choose the isotonic saline as a rehydration fluid.Conclusion: Genetic analysis presumably confirmed the diagnosis of NDI in every patient of the studied cohort. A plea of early identifying NDI confirmed by phenotype and genotype, and consequently optimize the treatment.

The Urfold: Structural Similarity Just above the Superfold Level?

OverviewWe suspect that there is a level of granularity of protein structure intermediate between the classical levels of ‘architecture’ and ‘topology’, as reflected in such phenomena as extensive 3D structural similarity above the level of (super)folds. Here, we examine this notion of architectural identity despite topological variability, starting with a concept that we call the ‘Urfold’. We believe that this model could offer a new conceptual approach for protein structural analysis and classification: indeed, the Urfold concept may help reconcile various phenomena that have been frequently recognized or debated for years, such as the precise meaning of ‘significant’ structural overlap and the degree of continuity of fold space. More broadly, the role of structural similarity in sequence/structure/function evolution has been studied via many models over the years; the Urfold may help synthesize these models into a generalized, consistent framework, by addressing a conceptual gap that we believe exists between the architecture and topology levels of structural classification schemes.

First hybrid complete genome ofAeromonas veroniireveals chromosome-mediated novel structural variantmcr-3.19from human clinical specimen

BackgroundRecent findings substantiate the origin of plasmid-mediated colistin resistance genemcr-3from Aeromonads. The present study aimed to screen the plasmid-mediated colistin resistance among 30 clinical multidrug resistant (MDR)Aeromonas spp.ResultsThe presence ofmcr-1, mcr-2, mcr-3, and mcr-4were screened by PCR, which revealedmcr-3in a colistin susceptible isolate (FC951). All other isolates were negative formcrgenes. Sequencing of FC951 revealed thatmcr-3(mcr-3.19) identified was different from previously reported variants and had 95.62 and 95.28% nucleotide similarity withmcr-3.3andmcr-3.10gene. A hybrid assembly using IonTorrent and MinION reads revealed structural genetic information ofmcr-3.19with an insertion of ISAs18within the gene. Due to this,mcr-3.19was non-expressive which makes FC951 susceptible to colistin. Further,in silicosequence and protein structural analysis confirmed the new variant. To the best of our knowledge, this is the first report on novelmcr-3variant (mcr-3.19).ConclusionsThe significant role ofmcr-like genes in differentAeromonasspecies remains unknown and needs additional investigation to understand the insights on colistin resistance mechanism.