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. 2020 Dec;191(5):e124-e128.
doi: 10.1111/bjh.17090. Epub 2020 Nov 20.

A Sardinian founder mutation in glycoprotein Ib platelet subunit beta (GP1BB) that impacts thrombocytopenia

Fabio Busonero  1 , Maristella Steri  1 , Valeria Orrù  1 , Gabriella Sole  1 , Stefania Olla  1 , Michele Marongiu  1 , Andrea Maschio  1 , Carlo Sidore  1 , Sandra Lai  1 , Antonella Mulas  1 , Magdalena Zoledziewska  1 , Matteo Floris  1   2 , Mauro Pala  1 , Paola Forabosco  1 , Isadora Asunis  1 , Maristella Pitzalis  1 , Francesca Deidda  1 , Marco Masala  1 , Cristian Antonio Caria  1 , Susanna Barella  3 , Goncalo R Abecasis  4 , David Schlessinger  5 , Serena Sanna  1 , Edoardo Fiorillo  1 , Francesco Cucca  1   2
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A Sardinian founder mutation in glycoprotein Ib platelet subunit beta (GP1BB) that impacts thrombocytopenia

Fabio Busonero et al. Br J Haematol. 2020 Dec.
No abstract available

Keywords: GP1BB; bernard-Soulier syndrome; functional studies; genetic analysis; platelet count; platelet glycoproteins.

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Conflict of interest statement

Conflict of interest

The authors declare no competing interests.

Figures

Fig 1.
Fig 1.
Effects of chr22:19711445 genotype on platelet-related phenotypes. (A) Platelet (PLT) count distribution stratified on 57 heterozygous carriers and 6471 homozygous wild types. (B) Mean platelet volume (MPV) distribution stratified on 28 heterozygous carriers and 1972 homozygous wild types. Basal expression levels of the main GPIb-IX-V receptor glycoproteins on resting platelets: (C) GPIX on 23 carriers and 23 controls, and (D) GPIbα on 24 carriers and 24 controls. (E–G) Expression levels of the most relevant platelet activation-dependent markers (activated αIIbβ3, P-selectin and granulophysin), in basal conditions and after stimulation with ADP. Violin plots represent the distribution of the data; the boxplots inside report the median value as a dot, the interquartile range (IQR) as a box, the 1st quartile −1·5 IQR and the 3rd quartile +1·5 IQR as whiskers. **P < 0·01, ***P < 0·001. MFI, median fluorescence intensity.
Fig 2.
Fig 2.
GPIbβ amino acid sequence with BSS-causing mutations and molecular modelling analyses. (A) Positions of the mutations within the coding regions of platelet glycoprotein (GP)Ibβ according to National Center for Biotechnology Information (NCBI) Reference Sequence, NP_000398.1. The different domains are indicated with different patterns. Different types of mutation are colour-coded; highlighted in yellow is the Proline27 to Serine27 substitution (P27S) described here first. Known mutations were obtained from: Savoia et al., 2014; Sivapalaratnam et al., 2017; Bragadottir et al., 2015; Qiao et al., 2015; Kunishima et al., 2001; Ferrari et al., 2018; and Bastida et al., 2018. (B) Three-dimensional structure of GPIbβ sequence, colour-coded according to the schematic representation in (A). (C) X-ray structure of protein (26–143 aa code 3RFE) showing the impact of p.P27S on GPIbβ glycoprotein conformation; in particular, the superposition between the first (teal) and last (yellow) frame of the molecular dynamics for the p.P27S protein (left), and the superposition between the first (pink) and last (green) frame for the wild-type (WT) protein (right) are reported.
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References

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