a cDNA change.
b % minor allele frequency.
c Fisher's exact test.
* p<0.05.

In human aging and longevity, the amino acid change (p.V465A) in GABRR3 was predicted to be benign according to the SIFT and PolyPhen2. However, the variation occurs at residue 465 of a 467 amino acid integral membrane protein. Transmembrane-predicting programs suggest that this residue will be right at the end of the last transmembrane helix. It is conceivable that V to A substitution might introduce minor flexibility in this region by leaving a hydrophobic pocket to fill. If the C-terminus interacts with a factor like a PDZ domain, which recognizes C-terminal sequence motifs, it could have an impact on GABBR3 function. Further functional analysis will be needed to uncover molecular mechanisms by which these variants lead to changes in protein function and contribute to longevity.

Interestingly, none of the reported mutations from HNPCC patients are near this region, suggesting that the centenarian-specific nsSNP may have a gain-of-function property beneficial to long lifespan.

GABRR3 encodes the rho3 subunit of GABA-rho A receptor, which is composed of five subunits. The five subunits can be made up with any three kinds of subunit (rho 1, 2, 3) as a homo-hetero pentamer complex. The GABA-rho receptor is a kind of ionotropic GABA receptor which responds to the neurotransmitter gamma-aminobutyric acid (GABA). About of neurons in the hippocampus are inhibitory and most of them are GABAergic. It was reported that there was an aging-related change in GABA receptor composition and that the GABA receptor could be relevant to AD pathogenesis (Rissman and Mobley, 2011).

The discovery of significant depletion of GABRR3 (p.V465A) in centenarians as compared to controls suggests its potential role in longevity. We also identified 13 novel nsSNPs that were detected only in centenarians but not in controls (Table 2), although none of them...