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. 2013 May 7;8(5):e63897.
doi: 10.1371/journal.pone.0063897. Print 2013.

Structural and population-based evaluations of TBC1D1 p.Arg125Trp

Tom G Richardson  1 , Elaine C Thomas, Richard B Sessions, Debbie A Lawlor, Jeremy M Tavaré, Ian N M Day
Affiliations

Structural and population-based evaluations of TBC1D1 p.Arg125Trp

Tom G Richardson et al. PLoS One. .

Abstract

Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother-offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m(2) (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (χ(2) = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Location of R125 in the homology model of human TBC1D1 PTB1.
(A) Homology based model of TBC1D1 PTB domain (residues 13–161) predicted by Robetta server (http://robetta.bakerlab.org/). The R125 residue (red) is orientated towards the cleft formed between β5 and α2 (purple). (B) Solved structure of IRS-1 PTB domain (PDB ID: 1IRS, [47]). The IL-4 phosphopeptide (red) lies within the cleft formed between the β5 and α2 (purple), a type I β turn redirects the peptide such that the phosphorylated Tyr (shown) is orientated towards the β6/β7 loop.
Figure 2
Figure 2. Kernel Density Plot to Show BMI Distribution at mean age 15.5 years between Homozygous Genotypes.
See this image and copyright information in PMC

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