A Sardinian founder mutation in GP1BB that impacts thrombocytopenia.
By
Fabio Busonero,
Maristella Steri,
Valeria Orru,
Gabriella Sole,
Stefani Olla,
Michele Marongiu,
Carlo Sidore,
Sandra Lai,
Antonella Mulas,
Andrea Maschio,
Magdalena Zoledziewska,
Matteo Floris,
Mauro Pala,
Paola Forabosco,
Isadora Asunis,
Maristella Pitzalis,
Francesca Deidda,
Marco Masala,
Cristian Antonio Caria,
Susanna Barella,
Gonçalo R. Abecasis,
David Schlessinger,
Serena Sanna,
Edoardo Fiorillo,
Francesco Cucca
Posted 08 Jul 2020
medRxiv DOI: 10.1101/2020.07.06.20143263
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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