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.
A Sardinian founder mutation in glycoprotein Ib platelet subunit beta(GP1BB) that impacts thrombocytopenia
Busonero Fabio;Orru Valeria;Sole Gabriella;Olla Stefania;Marongiu Michele;Maschio Andrea;Sidore Carlo;Lai Sandra;Mulas Antonella;Zoledziewska Magdalena;Floris Matteo;Pala Mauro;Forabosco Paola;Asunis Isadora;Pitzalis Maristella;Deidda Francesca;Masala Marco;Caria Cristian Antonio;Sanna Serena;Fiorillo Edoardo;Cucca Francesco
2020
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.