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To investigate the genetic regulation of platelet (PLT) levels we carried out a whole-genome association analysis in 6,528 Sardinians from the general population of the Lanusei valley. We found 6 variants significantly influencing PLT levels, including a novel rare missense mutation (p.Pro27Ser) in the GP1BB protein that is associated with PLT reduction (P=1.17x10-16). This mutation is rare in the SardiNIA population cohort (frequency of 0.45%), even rarer in the rest of the Sardinian island (frequency of 0.16%), and not reported elsewhere. Notably, GP1BB is involved in Bernard-Soulier syndrome (BSS), a rare autosomal recessive bleeding disorder caused by a defect in the platelet GPIb-IX-V protein complex. Consistently, the 57 identified individuals heterozygous for the p.P27S mutation showed mild thrombocytopenia, morphologically enlarged platelets (P=2.13x10-10), and reduced expression of two GPIb-IX-V-complex components: GPIb (-26.51%, P=3.66x10-8) and GPIX (-24.69%, P=2.66x10-6). Molecular modeling infers a corresponding reduction in the stability of GP1BB. These observations predict that in homozygosity as well as in individuals carrying specific compound heterozygous configurations, this variant likely causes BSS.

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