Dataset Information

Exhaustive non-synonymous variants functionality prediction enables high resolution characterization of the neurofibromin architecture.

ABSTRACT:

Background

Neurofibromatosis type I (NF1) is caused by heterozygous loss-of-function variants in the NF1 gene encoding neurofibromin which serves as a tumor suppressor that inhibits RAS signaling and regulates cell proliferation and differentiation. While, the only well-established functional domain in the NF1 protein is the GAP-related domain (GRD), most of the identified non-truncating disease-causing variants are located outside of this domain, supporting the existence of other important disease-associated domains. Identifying these domains may reveal novel functions of NF1.

Methods

By implementing inferential statistics combined with machine-learning methods, we developed a novel NF1-specific functional prediction model that focuses on nonsynonymous single nucleotide variants (SNVs). The model enables annotating all possible NF1 nonsynonymous variants, thus mapping the range of pathogenic non-truncating variants at the codon level across the NF1 gene.

Findings

The generated model demonstrates high absolute prediction value for missense and splice-site variations (area under the ROC curve of 0.96) outperforming 14 other established models. By reviewing the entire dataset of nonsynonymous variants, two novel domains (Armadillo type fold 1 and 2) were identified as being associated with pathogenicity (OR 1.86; CI 1.04 to 3.34 and OR 2.08; CI 1.08 to 4.04, respectively; P < .05). Specific exons and codons associated with increased pathogenicity were also detected along the gene inside and outside the GRD domain.

Interpretation

The developed model, enabled better prediction of pathogenicity for variants in NF1 gene, as well as elucidation of novel NF1-associated domains in addition to the GRD. FUND: This work was partially supported by the Kahn foundation. DGE is supported by the all Manchester NIHR Biomedical Research Centre (IS-brC-1215-20007).

SUBMITTER: Isakov O

PROVIDER: S-EPMC6197713 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Exhaustive non-synonymous variants functionality prediction enables high resolution characterization of the neurofibromin architecture.

Isakov Ofer O Wallis Deeann D Evans D Gareth DG Ben-Shachar Shay S

EBioMedicine 20180928

<h4>Background</h4>Neurofibromatosis type I (NF1) is caused by heterozygous loss-of-function variants in the NF1 gene encoding neurofibromin which serves as a tumor suppressor that inhibits RAS signaling and regulates cell proliferation and differentiation. While, the only well-established functional domain in the NF1 protein is the GAP-related domain (GRD), most of the identified non-truncating disease-causing variants are located outside of this domain, supporting the existence of other import ...[more]

PMID: 30274822

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Project description:Muscle architecture is an important component of muscle function, and recent studies have shown changes in muscle architecture with fatigue. The stretch-shortening cycle is a natural way to study human locomotion, but little is known about how muscle architecture is affected by this type of exercise. This study investigated potential changes in medial gastrocnemius (MG) muscle architecture after exhaustive stretch-shortening cycle exercise. Male athletes (n = 10) performed maximal voluntary contractions (MVC) and maximal drop jump (DJ) tests before and after an exercise task consisting of 100 maximal DJs followed by successive rebound jumping to 70% of the initial maximal height. The exercise task ceased upon failure to jump to 50% of maximal height or volitional fatigue. Muscle architecture of MG was measured using ultrasonography at rest and during MVC, and performance variables were calculated via a force plate and motion analysis. After SSC exercise, MVC (-13.1%; p = 0.005; dz = 1.30), rebound jump height (-14.8%, p = 0.004; dz = 1.32), and ankle joint stiffness (-26.3%; p = 0.008; dz = 1.30) decreased. Ankle joint range of motion (+20.2%; p = 0.011; dz = 1.09) and MG muscle-tendon unit length (+12.0%; p = 0.037; dz = 0.91) during the braking phase of DJ, the immediate drop-off in impact force (termed peak force reduction) (?27.3%; p = 0.033; dz = 0.86), and lactate (+9.5 mmol/L; p < 0.001; dz = 3.58) increased. Fascicle length increased at rest (+4.9%; p = 0.013; dz = 1.16) and during MVC (+6.8%; p = 0.048; dz = 0.85). Pennation angle decreased at rest (-6.5%; p = 0.034, dz = 0.93) and during MVC (-9.8%; p = 0.012; dz = 1.35). No changes in muscle thickness were found at rest (-2.6%; p = 0.066; dz = 0.77) or during MVC (-1.6%; p = 0.204; dz = 0.49). The greater MG muscle-tendon stretch during the DJ braking phase after exercise indicates that muscle damage likely occurred. The lower peak force reduction and ankle joint stiffness, indicative of decreased active stiffness, suggests activation was likely reduced, causing fascicles to shorten less during MVC.

Dataset Information

Exhaustive non-synonymous variants functionality prediction enables high resolution characterization of the neurofibromin architecture.

Background

Methods

Findings

Interpretation

Publications

Exhaustive non-synonymous variants functionality prediction enables high resolution characterization of the neurofibromin architecture.

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