The Lamin B receptor (LBR) is a pivotal architectural protein in the nuclear envelope. Mutations in the Lamin B receptor lead to nuclear hyposegmentation (Pelger-Huët anomaly). We have exactly quantified the nuclear lobulation in neutrophils from individuals with 0, 1, 2 and 3 functional copies of the lamin B receptor gene and analyzed the effect of different mutation types. Our data demonstrate that there is a highly significant gene-dosage effect between the gene copy number and the nuclear segmentation index of neutrophils. This finding is paralleled by a dose-dependent increase in LBR protein and staining intensity of the nuclear membrane in corresponding lymphoblastoid cell lines, which demonstrates a significant correlation on the protein level as well. We further show that LBR expression continually increases during granulopoiesis in vitro from human precursor cells with ovoid nuclei to multi-segmented neutrophil nuclei 11 days later, indicating relevance for regular human granulopoiesis. Altogether, LBR is a unique model that will allow the systematic study of gene-dosage effects and of modifying endogeneous and exogeneous factors on granulopoiesis.

中文翻译：

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零至三个功能性 LBR 基因的体内和体外剂量效应


核纤层蛋白 B 受体 (LBR) 是核膜中的关键结构蛋白。核纤层蛋白 B 受体突变会导致核分叶不足（Pelger-Huët 异常）。我们准确地量化了具有 0、1、2 和 3 个核纤层蛋白 B 受体基因功能拷贝的个体的中性粒细胞核分叶，并分析了不同突变类型的影响。我们的数据表明，基因拷贝数和中性粒细胞核分割指数之间存在高度显着的基因剂量效应。这一发现与相应淋巴母细胞系中 LBR 蛋白和核膜染色强度呈剂量依赖性增加相一致，这也表明蛋白质水平存在显着相关性。我们进一步表明，在体外粒细胞生成过程中，从具有卵形核的人类前体细胞到 11 天后的多节段中性粒细胞核，LBR 表达持续增加，表明与常规人类粒细胞生成相关。总而言之，LBR 是一个独特的模型，可以系统地研究基因剂量效应以及修改内源性和外源性因素对粒细胞生成的影响。