Automated inference of molecular mechanisms of disease from amino acid substitutions

Li, Biao; Krishnan, Vidhya G.; Mort, Matthew; Xin, Fuxiao; Kamati, Kishore K.; Cooper, David Neil; Mooney, Sean D.; Radivojac, Predrag

doi:10.1093/bioinformatics/btp528

Cited by 730 publications

(669 citation statements)

References 56 publications

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“…Although 3 nm short-wavelength shifted as compared with WT, the spectral peak of absorbance for the R69H variant pigment lies within an acceptable experimental range (<5 nm). In contrast to our human data, bovine R69H rhodopsin was table 2 Bioinformatic analyses using three commonly used mutation programs of pathogenicity, SIFT, 37 PolyPhen2, 38 and MutPred, 39 shown previously to produce an abnormally translated protein in a baculovirus expression system. 34 However, we have been unable to confirm a role of R69H in the pathogenicity of retinal disease in Patient 4.…”

Section: Validation Of Functional Analysescontrasting

confidence: 76%

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Davies

Downes

et al. 2012

Genetics in Medicine

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original research articlePurpose: The interpretation of genetic information has always been challenging, but next-generation sequencing produces data on such a vast scale that many more variants of uncertain pathogenicity will be found. We exemplify this issue with reference to human rhodopsin, in which pathogenic mutations can lead to autosomal dominant retinitis pigmentosa.methods: Rhodopsin variants, with unknown pathogenicity, were found in patients by next-generation and Sanger sequencing and a multidisciplinary approach was used to determine their functional significance.Results: Four variants in rhodopsin were identified: F45L, P53R, R69H, and M39R, with the latter two substitutions being novel. We investigated the cellular transport and photopigment function of all four human substitutions and found that the F45L and R69H variants behave like wild-type and are highly unlikely to be pathogenic. By contrast, P53R (a de novo change) and M39R were retained in the endoplasmic reticulum with significantly reduced functionality and are clearly pathogenic.conclusion: Potential pathogenicity of variants requires careful assessment using clinical, genetic, and functional data. We suggest that a multidisciplinary pathway of assessment, using several functional assays, will be required if next-generation sequencing is to be used effectively, reliably, and safely in the clinical environment. 2012:14(11):891-899 Genet Med

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Section: Validation Of Functional Analysescontrasting

confidence: 76%

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Davies

Downes

et al. 2012

Genetics in Medicine

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“…Variant tolerance prediction methods included Mutation Taster [Schwarz et al, 2010], MutPred [Li et al, 2009], nsSNPAnalyzer [Bao et al, 2005], PhD-SNP [Capriotti et al, 2006], PMut [Ferrer-Costa et al, 2005], PolyPhen2 [Adzhubei et al, 2010], SIFT [Ng and Henikoff, 2003], SNAP [Bromberg and Rost, 2007], and SNPs&GO [Calabrese et al, 2009]. Sequence-based stability effect predictions were performed with SCPRED [Dosztányi et al, 1997], MUPRO [Cheng et al, 2006], and I-Mutant 3.0 [Capriotti et al, 2005], and structurebased predictions with SCide (stabilization centers) [Dosztanyi et al, 2003] and SRide (stabilizing residues) [Magyar et al, 2005] for MSH2 and MSH6 variants.…”

Section: Prediction Of Pathogenicitymentioning

confidence: 99%

Classification of mismatch repair gene missense variants with PON-MMR

Ali¹,

Olatubosun²,

Vihinen

2012

Hum. Mutat.

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“…After identification of variants, allele frequencies were assessed in controls using restriction endonuclease digestion (Ava II) or using HybProbe chemistry and a LightCycler (Roche, Mannheim, Germany). The significance of the identified variant p.R47W was assessed by considering the conservation of the affected amino acid, the nature and location of the change, its rarity assessed in own controls and population-based datasets, and the possible impact of the amino acid substitution by five different mutation prediction tools (Mutation Taster [9], MutPred [10], SIFT [11], Polyphen2 [12], and SNAP [13]). We analyzed p.R47W by checking two large population-based databases, dbSNP (release 138 at http://www.ncbi.nlm.nih.gov/snp) and the Exome Sequencing Project (ESP6500SI-V2 dataset) of the National Heart, Lung and Blood Institute (http://evs.gs.washington.edu/EVS/ [14]).…”

Section: Methodsmentioning

confidence: 99%

CCN1 Mutation is Associated with Atrial Septal Defect

et al. 2014

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The genetic basis of congenital heart disease remains unknown in most of the cases. Recently, a novel mouse model shed new light on the role of CCN1/CYR61, a matricellular regulatory factor, in cardiac morphogenesis. In a candidate gene approach, we analyzed a cohort of 143 patients with atrial septal defects (ASD) by sequencing the coding exons of CCN1. In addition to three frequent polymorphisms, we identified an extremely rare novel heterozygous missense mutation (c.139C>T; p.R47W) in one patient with severe ASD. The mutation leads to an exchange of residues with quite different properties in a highly conserved position of the Nterminal insulin-like growth factor binding protein (IGFBP) module. Further bioinformatic analysis, exclusion of known ASD disease genes as well as the exclusion of the mutation in a very high number of ethnically matched controls (more than 1000 individuals) and in public genetic databases indicates that the p.R47W variant is a probable disease-associated mutation. The report about ASD in mice in heterozygous Ccn1 +/-animals strongly supports this notion. Our study is the first to suggest a relationship between a probable CCN1 mutation and ASD. Our purpose here was to draw attention to CCN1, a gene that we believe may be important for genetic analysis in patients with congenital heart disease.

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Automated inference of molecular mechanisms of disease from amino acid substitutions

Abstract: predrag@indiana.edu; smooney@buckinstitute.org.

Cited by 730 publications

References 56 publications

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Next-generation sequencing in health-care delivery: lessons from the functional analysis of rhodopsin

Classification of mismatch repair gene missense variants with PON-MMR

CCN1 Mutation is Associated with Atrial Septal Defect

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