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首页> 外文期刊>Nucleus > Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein
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Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein

机译：引起格林伯格发育异常的突变，但不引起佩尔格异常，使酶与核膜蛋白的结构功能脱钩

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The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function interacting with chromatin and lamins, and an enzymatic function as a sterol reductase. Heterozygous LBR mutations cause nuclear hyposegmentation in neutrophils (Pelger anomaly), while homozygous mutations cause prenatal death with skeletal defects and abnormal sterol metabolism (Greenberg dysplasia). It has remained unclear whether the lethality in Greenberg dysplasia is due to cholesterol defects or altered nuclear morphology.To answer this question we characterized two LBR missense mutations and showed that they cause Greenberg dysplasia. Both mutations affect residues that are evolutionary conserved among sterol reductases. In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase deficient yeast, indicating an enzymatic defect. We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear structure. We studied Lbr in mouse embryos and demonstrate expression in skin and the developing skeletal system consistent with sites of histological changes in Greenberg dysplasia. Unexpectedly we found in disease-relevant cell types not only nuclear but also cytoplasmatic LBR localization. The cytoplasmatic LBR staining co-localized with ER-markers and is thus consistent with the sites of endogeneous sterol synthesis.?We conclude that LBR missense mutations can abolish sterol reductase activity, causing lethal Greenberg dysplasia but not Pelger anomaly. The findings separate the metabolic from the structural function and indicate that the sterol reductase activity is essential for human intrauterine development.
机译：核纤层蛋白B受体（LBR）是一种内核膜蛋白，具有与染色质和lamins相互作用的结构功能，以及作为固醇还原酶的酶促功能。杂合的LBR突变导致中性粒细胞核分裂低（Pelger异常），而纯合的突变导致产前死亡，并伴有骨骼缺陷和固醇代谢异常（格林伯格发育不良）。尚不清楚格林伯格发育不良的致死性是由于胆固醇缺陷还是核形态改变所致。为回答这个问题，我们对两个LBR错义突变进行了表征，并表明它们引起了格林伯格发育不良。两种突变都影响固醇还原酶之间进化保守的残基。与野生型LBR相反，这两个突变均未能挽救C14甾醇还原酶缺陷型酵母，表明存在酶促缺陷。除了对核结构的显着影响外，我们在携带者的父母中没有发现Pelger异常。我们研究了小鼠胚胎中的Lbr，并证明了其在皮肤和发育中的骨骼系统中的表达与格林伯格发育不良的组织学变化部位一致。出乎意料的是，我们发现与疾病相关的细胞类型不仅有核，而且还有胞质LBR定位。细胞质LBR染色与ER标记共定位，因此与内源性固醇合成位点一致。我们得出结论，LBR错义突变可以消除固醇还原酶活性，引起致命的格林伯格发育不良，但不能引起Pelger异常。这些发现将代谢与结构功能分开，表明固醇还原酶活性对于人类子宫内发育至关重要。

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