Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from −3.6 to −12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.

Lamin B1在核被膜的稳定性，基因表达的调节和神经发育中起着重要作用。LMNB1的重复或增加LMNB1表达的错义突变与常染色体显性白细胞营养不良有关。根据其在神经发生中的作用，推测LMNB1变异可能引起小头畸形。在这里，我们通过鉴定LMNB1中的从头突变来证实这一假设在七个具有明显原发性小头畸形（范围从-3.6到-12 SD）的个体中，其相对矮小的身材和不同程度的智力残疾和神经系统特征是其核心症状。在三个人的MRI上，皮质的回旋模式和异常的call体变简单了，这些人的表现型也更严重。对三个错义突变的功能分析表明，LMNB1核纤层的形成受损。位于LMNB1头组中的两个变体导致蛋白质核定位的减少和畸形核的增加。我们进一步证明位于线圈区的另一个突变导致先证淋巴母细胞中核浓缩频率增加和层粘连蛋白B1的稳态水平降低。LMNB1的从头突变导致对人类小头畸形相关的核包膜形成的显性和破坏性作用。这将LMNB1添加到与严重常染色体显性遗传小头畸形有关的基因列表中，并拓宽了lanopathies的表型谱。