scholarly journals A systematic genotype-phenotype map for missense variants in the human intellectual disability-associated gene GDI1

2021 ◽  
Author(s):  
Rachel A. Silverstein ◽  
Song Sun ◽  
Marta Verby ◽  
Jochen Weile ◽  
Yingzhou Wu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Amino Acid ◽  
Genetic Diseases ◽  
Computational Prediction ◽  
Structural Features ◽  
Single Amino Acid ◽  
Variants Of Unknown Significance ◽  
Large Numbers ◽  
Unknown Significance ◽  
Variant Effect

AbstractNext generation sequencing has become a common tool in the diagnosis of genetic diseases. However, for the vast majority of genetic variants that are discovered, a clinical interpretation is not available. Variant effect mapping allows the functional effects of large numbers of single amino acid variants to be characterized in parallel. Here, we employ a variant effect mapping framework, combining functional assays with machine learning, to assess the effects of 89% of all possible amino acid substitutions in the human intellectual disability-associated gene, GDI1. We show that the resulting variant effect map can be used to discriminate pathogenic from benign variants at levels of precision higher than those achieved by current computational prediction tools. Our variant effect map recovers known biochemical and structural features of GDI1 and reveals new structural regions which may be important for GDI1 function. We explore how this variant effect map can be used to aid in the interpretation of novel GDI1 variants as they are discovered, and to re-classify previously observed variants of unknown significance.

scholarly journals Antigen binding and idiotype analysis of antibodies obtained after electroporation of heavy and light chain genes encoding phosphocholine-specific antibodies: a model for T15-idiotype dominance.

1992 ◽  
Vol 176 (6) ◽  
pp. 1637-1643 ◽  
Author(s):  
J J Kenny ◽  
C M Moratz ◽  
G Guelde ◽  
C D O'Connell ◽  
J George ◽  
...  
Keyword(s):  
Immune Response ◽  
Amino Acid ◽  
B Cell ◽  
Molecular Model ◽  
Immunoglobulin M ◽  
Single Amino Acid ◽  
Primary Immune Response ◽  
Antigen Binding ◽  
Large Numbers ◽  
Genes Encoding

Antibodies bearing the T15 idiotype dominate the murine primary immune response to phosphocholine (PC). Analysis of antigen binding of antibodies derived from V1:DFL16.1:JH1 (VH1) germline and N region-derived variant heavy (H) chains and kappa 22, kappa 24, and kappa 8 light (L) chains demonstrates that the T15H:kappa 22L (T15) antibody binds PC at least 20-40 times better than other antibodies derived from alternate germline forms of the VH1 H chain and kappa 22, kappa 24, or kappa 8 L chains. To achieve affinities in the same range as the T15 antibody, kappa 24 and kappa 8 L chain-containing antibodies must have H chains derived from variant N region or somatically mutated VH1 genes. Single amino acid differences at the VD junction of the various germline and N region variant VH1 H chains dictate the L chain that can associate with the H chain to produce a PC-specific antibody. Several H:L combinations give rise to T15 or M167 idiotype-positive antibodies that lack specificity for PC, and single amino acid substitutions or insertions at the VH1:D junction result in the loss of T15 or M167 idiotopes. Based on these observations, our data support a molecular model involving both preferential gene rearrangement and antigen-driven B cell selection to explain T15 idiotype dominance in the immune response to PC. In the absence of N region diversification, large numbers of neonatal B cells bearing the T15H:kappa 22L surface immunoglobulin M (sIgM) receptors would be selected and expanded by autologous or environmental PC antigen into the long-lived peripheral B cell pool.

scholarly journals Computational prediction of the tolerance to amino-acid deletion in green-fluorescent protein

2016 ◽  
Author(s):  
Eleisha L. Jackson ◽  
Stephanie J. Spielman ◽  
Claus O. Wilke
Keyword(s):  
Green Fluorescent Protein ◽  
Protein Structure ◽  
Amino Acid ◽  
Protein Design ◽  
Fluorescent Protein ◽  
Computational Prediction ◽  
Single Amino Acid ◽  
Dimensional Structure ◽  
Amino Acid Deletion ◽  
Green Fluorescent

AbstractProteins evolve through two primary mechanisms: substitution, where mutations alter a protein’s amino-acid sequence, and insertions and deletions (indels), where amino acids are either added to or removed from the sequence. Protein structure has been shown to influence the rate at which substitutions accumulate across sites in proteins, but whether structure similarly constrains the occurrence of indels has not been rigorously studied. Here, we investigate the extent to which structural properties known to covary with protein evolutionary rates might also predict protein tolerance to indels. Specifically, we analyze a publicly available dataset of single–amino-acid deletion mutations in enhanced green fluorescent protein (eGFP) to assess how well the functional effect of deletions can be predicted from protein structure. We find that weighted contact number (WCN), which measures how densely packed a residue is within the protein’s three-dimensional structure, provides the best single predictor for whether eGFP will tolerate a given deletion. We additionally find that using protein design to explicitly model deletions results in improved predictions of functional status when combined with other structural predictors. Our work suggests that structure plays fundamental role in constraining deletions at sites in proteins, and further that similar biophysical constraints influence both substitutions and deletions. This study therefore provides a solid foundation for future work to examine how protein structure influences tolerance of more complex indel events, such as insertions or large deletions.

scholarly journals Structural features of single amino acid repeats in proteins

FEBS Letters ◽  
1999 ◽  
Vol 448 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Juan A Subirana ◽  
Jaume Palau
Keyword(s):  
Amino Acid ◽  
Structural Features ◽  
Single Amino Acid ◽  
Amino Acid Repeats

scholarly journals Characterization of insulins and proglucagon-derived peptides from a phylogenetically ancient fish, the paddlefish (Polyodon spathula)

1994 ◽  
Vol 300 (2) ◽  
pp. 339-345 ◽  
Author(s):  
T M Nguyen ◽  
T P Mommsen ◽  
S M Mims ◽  
J M Conlon
Keyword(s):  
Amino Acid ◽  
Amino Acid Substitution ◽  
Teleost Fish ◽  
Structural Similarity ◽  
Structural Features ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Molecular Forms ◽  
Polyodon Spathula ◽  
The North

The North American paddlefish, Polyodon spathula (Order Acipenseriformes) is an extant representative of a group of primitive Actinopterygian (ray-finned) fish that probably shared a common ancestor with present-day teleosts. Two molecular forms of insulin which differ by a single amino acid substitution, His or Asp at position 15 of the A chain, were isolated from the pancreas of the paddlefish. Paddlefish insulins show greatest structural similarity to insulin from the garfish (order Lepisosteiformes) and resemble mammalian insulins more strongly than do insulins from teleost fish. The primary structures of several proglucagon-derived peptides, two molecular forms of glucagon which differ by the single amino acid substitution Arg18-->Ser, and glucagon-like peptide, have been less well conserved during evolution. The paddlefish glucagons contain 31 amino acid residues, rather than the usual 29, and show several structural features, such as Met5, Glu24 and Gly29, not previously observed in glucagons from other species. In spite of considerable differences in structure between paddlefish and mammalian glucagons (10 or 11 amino acid substitutions), both paddlefish glucagons are equally as effective as bovine glucagon in stimulating glycogenolysis in dispersed hepatocytes from the teleost fish Sebastes caurinus (rockfish). However, the substitution Arg18-->Ser in the paddlefish glucagon results in a 6-fold decrease in potency in this system.

scholarly journals Determination of the secondary structure of selected melittin analogues with different haemolytic activities

1994 ◽  
Vol 299 (2) ◽  
pp. 587-591 ◽  
Author(s):  
E Pérez-Payá ◽  
R A Houghten ◽  
S E Blondelle
Keyword(s):  
Amino Acid ◽  
Secondary Structure ◽  
Structural Features ◽  
The Self ◽  
Single Amino Acid ◽  
Haemolytic Activity ◽  
Phospholipid Membrane ◽  
Hydrophobic Residues ◽  
Self Association

In earlier studies, we have reported that minor modifications in the amino acid sequence of melittin result in dramatic changes in its biological activity. In the current study, we have investigated the secondary structure of melittin analogues with either increased or decreased haemolytic activity in order to further our understanding of the structural features involved in the binding and/or insertion of peptides into a phospholipid membrane from solution. This was accomplished by analysing the c.d. spectra of the analogues in solutions of various ionic strength and, separately, in the presence of micelles. These studies permit the assessment of the effect of small sequence modifications (i.e. single amino acid omission or substitution) on the self-association-induced secondary structure of melittin in aqueous solution, as well as its binding affinity to micelles. It was found that amphipathicity, as well as interchain distances and the orientation of hydrophobic residues, were involved in the induction of stabilized structures.

scholarly journals P.071 Novel mutations in SPG7 identified from patients with late-onset spasticity

2018 ◽  
Vol 45 (s2) ◽  
pp. S35-S35
Author(s):  
MM Almomen ◽  
KA Martens ◽  
A Hanson ◽  
L Korngut ◽  
G pfeffer
Keyword(s):  
Cerebellar Ataxia ◽  
Late Onset ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Transcript Level ◽  
Progressive External Ophthalmoplegia ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Leg Weakness

Background: Hereditary spastic paraplegia (HSP) is a group of genetic diseases that cause progressive degeneration of the corticospinal tract. Historically, this disease was divided into two types:the classic subtype, with leg weakness and hypertonic bladder, and the complicated subtype, with features such as cerebellar ataxia or optic atrophy.Mutations in SPG7 (encoding paraplegin) leads to complicated HSP causing cerebellar ataxia, progressive external ophthalmoplegia in addition to the classical symptoms. AFG3L2 is a binding partner of paraplegin and mutations in AFG3L2 cause a similar syndrome Methods: From a neurogenetic clinic , we identified 11 patients with late-onset HSP. Sequencing of SPG7 and AFG3L2 was performed using a customised assay, and/or clinical diagnostic sequencing panels.SPG7 transcript level quantification was performed from whole blood RNA on a digital droplet qPCR system. Results: We identified 4 patients with pathogenic variants or variants of unknown significance in SPG7. No AFG3L2 mutations were identified. We provide evidence for pathogenicity for three mutations that were not previously associated with SPG7-related disease, based on their occurrence in context of the correct phenotype, and the reduction of transcript levels measured with RT-qPCR.A curious association of the heterozygous p.Gly349Ser mutation in association with an ALS-like syndrome is reported. Conclusions:SPG7 mutations sequencing has high diagnostic yield in late onset paraparesis

scholarly journals High Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance

2017 ◽  
Author(s):  
Carlos G. Vanoye ◽  
Reshma R. Desai ◽  
Katarina L. Fabre ◽  
Franck Potet ◽  
Jean-Marc DeKeyser ◽  
...  
Keyword(s):  
High Throughput ◽  
Genetic Diseases ◽  
Functional Evaluation ◽  
Loss Of Function ◽  
Gene Variation ◽  
Variants Of Unknown Significance ◽  
Cardiac Ion Channels ◽  
Unknown Significance ◽  
High Level

ABSTRACTBackgroundThe explosive growth in known human gene variation presents enormous challenges to current approaches for variant classification that impact diagnosis and treatment of many genetic diseases. For disorders caused by mutations in cardiac ion channels, such as congenital long-QT syndrome (LQTS), in vitro electrophysiological evidence has high value in discriminating pathogenic from benign variants, but these data are often lacking because assays are cost-, time- and labor-intensive.Methods and ResultsWe implemented a strategy for performing high throughput, functional evaluations of ion channel variants that repurposed an automated electrophysiology platform developed previously for drug discovery. We demonstrated success of this approach by evaluating 78 variants in KCNQ1, a major LQTS gene. We benchmarked our results with traditional electrophysiological approaches and observed a high level of concordance. Our results provided functional data useful for classifying ~70% of previously unstudied KCNQ1 variants annotated with uninformative descriptions in the public database ClinVar. Further, we show that rare and ultra-rare KCNQ1 variants in the general population exhibit functional properties ranging from normal to severe loss-of-function indicating that allele frequency is not a reliable predictor of channel function.ConclusionsOur results illustrate an efficient and high throughput paradigm linking genotype to function for a human cardiac channelopathy that will enable data-driven classification of large numbers of variants and create new opportunities for precision medicine.

scholarly journals Computational prediction of the effect of amino acid changes on the binding affinity between SARS-CoV-2 spike protein and the human ACE2 receptor

2021 ◽  
Author(s):  
Chen Chen ◽  
Veda Sheeresh Boorla ◽  
Deepro Banerjee ◽  
Ratul Chowdhury ◽  
Victoria S Cavener ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Affinity ◽  
Viral Entry ◽  
Computational Prediction ◽  
Single Amino Acid ◽  
Binding Affinities ◽  
Generalized Born ◽  
The Public ◽  
Affinity Change ◽  
Multiple Amino Acid

The association of the receptor binding domain (RBD) of SARS-CoV-2 viral spike with human angiotensin converting enzyme (hACE2) represents the first required step for viral entry. Amino acid changes in the RBD have been implicated with increased infectivity and potential for immune evasion. Reliably predicting the effect of amino acid changes in the ability of the RBD to interact more strongly with the hACE2 receptor can help assess the public health implications and the potential for spillover and adaptation into other animals. Here, we introduce a two-step framework that first relies on 48 independent 4-ns molecular dynamics (MD) trajectories of RBD-hACE2 variants to collect binding energy terms decomposed into Coulombic, covalent, van der Waals, lipophilic, generalized Born electrostatic solvation, hydrogen-bonding, π-π packing and self-contact correction terms. The second step implements a neural network to classify and quantitatively predict binding affinity using the decomposed energy terms as descriptors. The computational base achieves an accuracy of 82.2% in terms of correctly classifying single amino-acid substitution variants of the RBD as worsening or improving binding affinity for hACE2 and a correlation coefficient r of 0.69 between predicted and experimentally calculated binding affinities. Both metrics are calculated using a 5-fold cross validation test. Our method thus sets up a framework for effectively screening binding affinity change with unknown single and multiple amino-acid changes. This can be a very valuable tool to predict host adaptation and zoonotic spillover of current and future SARS-CoV-2 variants.

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