SuSPect: Enhanced Prediction of Single Amino Acid Variant (SAV) Phenotype Using Network Features

Yates, Christopher M.; Filippis, Ioannis; Kelley, Lawrence A.; Sternberg, Michael J.E.

doi:10.1016/j.jmb.2014.04.026

Cited by 199 publications

(167 citation statements)

References 56 publications

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“…Positions resulting in protein-altering changes were identified using the Ensembl Variant Effect Predictor (version 78) and variants shared between family members were annotated using custom scripts. The predicted functional consequences of missense variants were assessed using SIFT, 21 CADD, 22 and SuSPect 23 algorithms.…”

Section: Sequence Alignment and Analysismentioning

confidence: 99%

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Speedy

Kinnersley

Chubb

et al. 2016

Blood

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Key Points• Germ line loss-of-function mutations in shelterin genes occur in a subset of families with CLL.• Telomere dysregulation is further implicated in CLL predisposition.Chronic lymphocytic leukemia (CLL) can be familial; however, thus far no rare germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (POT1) co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift, and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P 5

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Section: Sequence Alignment and Analysismentioning

confidence: 99%

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Speedy

Kinnersley

Chubb

et al. 2016

Blood

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“…Phylogenetic trees, sequence alignment and phenotypic prediction were carried out using Phylogeny.fr (Dereeper et al, 2008(Dereeper et al, , 2010, PRALINE (CIBVU) and SuSPect (Yates et al, 2014), respectively.…”

Section: Phylogenetic Analysismentioning

confidence: 99%

aura/mid1ip1L regulates the cytoskeleton at the zebrafish egg-to-embryo transition

2016

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Embryos from females homozygous for a recessive maternal-effect mutation in the gene aura exhibit defects including reduced cortical integrity, defective cortical granule (CG) release upon egg activation, failure to complete cytokinesis, and abnormal cell wound healing. Subcellular analysis shows that the cytokinesis defects observed in aura mutants are associated with aberrant cytoskeletal reorganization during furrow maturation, including abnormal F-actin enrichment and microtubule reorganization. Cortical F-actin prior to furrow formation fails to exhibit a normal transition into F-actin-rich arcs, and drug inhibition is consistent with aura function promoting F-actin polymerization and/or stabilization. In mutants, components of exocytic and endocytic vesicles, such as Vamp2, Clathrin and Dynamin, are sequestered in unreleased CGs, indicating a need for CG recycling in the normal redistribution of these factors. However, the exocytic targeting factor Rab11 is recruited to the furrow plane normally at the tip of bundling microtubules, suggesting an alternate anchoring mechanism independent of membrane recycling. A positional cloning approach indicates that the mutation in aura is associated with a truncation of Mid1 Interacting Protein 1L (Mid1ip1L), previously identified as an interactor of the X-linked Opitz G/BBB syndrome gene Mid1. A Cas9/CRISPR-induced mutant allele in mid1ip1L fails to complement the originally isolated aura maternal-effect mutation, confirming gene assignment. Mid1ip1L protein localizes to cortical F-actin aggregates, consistent with a direct role in cytoskeletal regulation. Our studies indicate that maternally provided aura/mid1ip1L acts during the reorganization of the cytoskeleton at the egg-to-embryo transition and highlight the importance of cytoskeletal dynamics and membrane recycling during this developmental period.

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“…Sequence conservation is used to predict which mutations can be tolerated within a protein structure, and similarly, protein structures have been used for estimating how disruptive a missense mutation may be [15,[17][18][19][20]. Techniques originally developed to predict the consequences of amino-acid changes observed in SNPs and Mendelian genetic diseases, have been applied to cancer mutations, but have often failed to provide sufficiently reliable prediction.…”

Section: Identifying Driver Mutationsmentioning

confidence: 99%

Mutational patterns in oncogenes and tumour suppressors

Baeissa

Benstead-Hume

Richardson

et al. 2016

Biochemical Society Transactions

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All cancers depend upon mutations in critical genes, which confer a selective advantage to the tumour cell. Knowledge of these mutations is crucial to understanding the biology of cancer initiation and progression, and to the development of targeted therapeutic strategies. The key to understanding the contribution of a disease-associated mutation to the development and progression of cancer, comes from an understanding of the consequences of that mutation on the function of the affected protein, and the impact on the pathways in which that protein is involved.In this paper we examine the mutation patterns observed in oncogenes and tumour suppressors, and discuss different approaches that have been developed to identify driver mutations within cancers that contribute to the disease progress. We also discuss the MOKCa database where we have developed an automatic pipeline that structurally and functionally annotates all proteins from the human proteome that are mutated in cancer.

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SuSPect: Enhanced Prediction of Single Amino Acid Variant (SAV) Phenotype Using Network Features

Cited by 199 publications

References 56 publications

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

aura/mid1ip1L regulates the cytoskeleton at the zebrafish egg-to-embryo transition

Mutational patterns in oncogenes and tumour suppressors

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