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: GPIbα (-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.

中文翻译：

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GP1BB中的撒丁岛创始人突变，影响血小板减少症。

为了研究血小板（PLT）水平的遗传调控，我们在Lanusei山谷总人口的6,528名撒丁岛人中进行了全基因组关联分析。我们发现了6种显着影响PLT水平的变体，包括GP1BB蛋白中与PLT减少相关的新型罕见错义突变（p.Pro27Ser）（P = 1.17x10-16）。此突变在SardiNIA人群队列中很少见（频率为0.45％），在撒丁岛其他地区（频率为0.16％）则更罕见，在其他地方也未见报道。值得注意的是，GP1BB与Bernard-Soulier综合征（BSS）有关，该综合征是一种罕见的常染色体隐性出血性疾病，由血小板GPIb-IX-V蛋白复合物的缺陷引起。一致地，已鉴定出的p.P27S突变杂合子的57个人显示出轻度血小板减少症，形态上扩大的血小板（P = 2.13x10-10），并减少了两种GPIb-IX-V复合成分的表达：GPIbα（-26.51％，P = 3.66x10-8）和GPIX（-24.69％，P = 2.66x10 -6）。分子模型推断GP1BB的稳定性相应降低。这些观察结果预测，在纯合性以及携带特定化合物杂合子构型的个体中，此变异可能导致BSS。