Structural and population-based evaluations of TBC1D1 p.Arg125Trp

Area of Science:

• Genetics
• Obesity Research
• Molecular Pathogenesis

Background:

• Obesity is a major preventable cause of death globally.
• Genetic factors significantly influence obesity's molecular pathogenesis.
• A TBC1D1 gene variant (rs35859249, p.Arg125Trp) has been linked to familial obesity in women.

Purpose of the Study:

• To investigate the association of the TBC1D1 R125W variant with obesity in a European birth cohort.
• To predict the structural impact of the R125W mutation on the TBC1D1 phosphotyrosine-binding domain.
• To explore potential therapeutic targets for obesity by understanding genetic influences.

Main Methods:

• Utilized the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort (N=2,292 mother-offspring pairs).
• Employed the transmission disequilibrium test (TDT) for familial association analysis.
• Used linear and logistic regression to assess genotype association with adiposity measures (BMI, waist circumference, fat mass) and obesity odds.
• Generated structural predictions of the TBC1D1 PTB domain using Robetta, HHpred/MODELLER, and I-TASSER algorithms.

Main Results:

• Structural modeling indicated the R125W mutation is located in a functional region of the TBC1D1 PTB domain, potentially involved in protein:protein interactions.
• No significant association was found between the R125W variant and mean Body Mass Index (BMI) (P=0.05).
• The R125W variant did not show a significant association with the odds of obesity (P=0.96) or familial obesity (P=0.80) after adjusting for multiple comparisons.

Conclusions:

• The R125W mutation in TBC1D1 may influence effector protein binding.
• This study found no evidence linking the R125W variant to mean BMI or obesity risk in the general population.
• Further research is needed to fully elucidate the role of TBC1D1 in obesity pathogenesis.