Consequences of human genetic variations in KIAA0319L, encoding adeno-associated virus receptor, on AAV-mediated gene...

Adeno-associated virus (AAV) vectors mediate persistent gene expression in non-proliferating cells, but patients receiving identical vector doses exhibit variable responses. Our prior report of 69,442 genetic variants among 62 genes encoding host proteins affecting AAV gene transfer suggested that naturally occurring human genetic variants might modify AAV efficacy. We assessed 15 predicted deleterious variants of KIAA0319L, which encodes the AAV receptor (AAVR). Following transfection, cells were transduced with AAV serotypes 2, 5, 6, 8, 9, rh.10, and rh32.33. Four variants encoding nonsense mutations had significant gene transfer reductions by all serotypes except AAVR-independent AAVrh32.33. All 11 missense variants expressed full-length AAVR peptide, but several expressed significantly less protein than wild-type AAVR. Gene expression mediated by AAV8, 9, and rh.10 was commonly, but not uniformly, decreased by missense variants, while gene expression by AAV2 was significantly decreased only by Lys3Thr. None of the missense variants significantly decreased expression by AAV5 or AAV6. Interestingly, three missense variants mediated increases in gene expression: Ser1031Phe and Gly1022Arg with AAV5 and Ala563Val with AAV9. Neither variant increasing AAV5 transduction impacted initial cell binding. However, Ser1031Phe increased trafficking to the nucleus. In conclusion, human AAVR variations influence gene transfer and contribute to variable efficacy of gene therapy.