| Autor: |
Gabriella Sole, Marco Masala, Sandra Lai, Valeria Orrù, Francesca Deidda, Mauro Pala, Magdalena Zoledziewska, Antonella Mulas, Matteo Floris, Andrea Maschio, Edoardo Fiorillo, Serena Sanna, Gonçalo R. Abecasis, Michele Marongiu, Isadora Asunis, Carlo Sidore, Maristella Steri, Cristian Antonio Caria, Francesco Cucca, Paola Forabosco, Fabio Busonero, Susanna Barella, Maristella Pitzalis, David Schlessinger, Stefania Olla |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
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=1.17×10−16). 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=2.13×10−10), and reduced expression of two GPIb-IX-V-complex components: GPIbα (−26.51%, P=3.66×10−8) and GPIX (−24.69%, P=2.66×10−6). 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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