Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly)
Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly)
复制标题
DOI：
10.1038/ng925
复制
发表时间：
2002-08-01
期刊：
影响因子：
30.8
通讯作者：
Sperling, K
中科院分区：
文献类型：
--
作者：
Hoffmann, K;Dreger, CK;Sperling, K
Pelger-Huet异常（PHA; OMIM *169400）是一种常染色体显性遗传病，其特征是血液粒细胞核形状和染色质组织异常。患者表现为中性粒细胞核减少，染色质粗糙。纯合子个体有卵形中性粒细胞核，以及不同程度的发育迟缓、癫痫和骨骼异常（1-3）。绝种兔系的纯合子后代表现出严重的软骨营养不良、发育异常和产前和产后死亡率增加（4,5）。通过全基因组连锁扫描，我们发现PHA与染色体1q41-43相连。我们在编码层粘连蛋白B受体的LBR中发现了4个剪接位点、2个移码位点和2个无义突变。层粘连蛋白B受体（lamin B receptor， LBR）是固醇还原酶家族的一员(6)，在进化上是保守的，是内核膜的组成部分；它将异染色质和层状蛋白靶向核膜（7,8）。受PHA影响的杂合子个体的淋巴母细胞样细胞显示层蛋白B受体的表达减少，而PHA纯合子细胞仅含有微量的层蛋白B受体。我们发现层粘胶蛋白B受体的表达以剂量依赖的方式影响中性粒细胞核形状和染色质分布。我们的发现对理解核包膜-异染色质相互作用、白血病中pelger样疾病的发病机制(9)、感染（10）和毒性药物反应（11）以及中性粒细胞核形状的进化（12）具有重要意义。
Pelger-Huet anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities(1-3). Homozygous off-spring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality(4,5). Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family(6), is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane(7,8). Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia(9), infection(10) and toxic drug reactions(11), and the evolution of neutrophil nuclear shape(12).