ANKRD11 (ankyrin repeat domain 11) is a chromatin regulator and the only gene associated with KBG syndrome, a rare neurodevelopmental disorder. We have previously shown that Ankrd11 regulates murine embryonic cortical neurogenesis. Here, we show a novel olfactory bulb phenotype in a KBG syndrome mouse model and two diagnosed patients. Conditional knockout of Ankrd11 in murine embryonic neural stem cells leads to aberrant postnatal olfactory bulb development and reduced size due to reduction of the olfactory bulb granule cell layer. We further show that the rostral migratory stream has incomplete migration of neuroblasts, reduced cell proliferation as well as aberrant differentiation of neurons. This leads to reduced neuroblasts and neurons in the olfactory bulb granule cell layer. In vitro, Ankrd11-deficient neural stem cells from the postnatal subventricular zone display reduced migration, proliferation, and neurogenesis. Finally, we describe two clinically and molecularly confirmed KBG syndrome patients with anosmia and olfactory bulb and groove hypo-dysgenesis/agenesis. Our report provides evidence that Ankrd11 is a novel regulator of olfactory bulb development and neuroblast migration. Moreover, our study highlights a novel clinical sign of KBG syndrome linked to ANKRD11 perturbations in mice and humans.

中文翻译：

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KBG 综合征小鼠模型和患者的嗅球异常

ANKRD11（锚蛋白重复结构域 11）是一种染色质调节因子，也是与 KBG 综合征（一种罕见的神经发育障碍）相关的唯一基因。我们之前已经证明 Ankrd11 调节小鼠胚胎皮质神经发生。在这里，我们在 KBG 综合征小鼠模型和两名确诊患者中展示了一种新的嗅球表型。在小鼠胚胎神经干细胞中条件性敲除 Ankrd11 会导致出生后嗅球发育异常，并且由于嗅球颗粒细胞层减少而导致尺寸减小。我们进一步表明，喙部迁移流具有神经母细胞的不完全迁移、细胞增殖减少以及神经元的异常分化。这导致嗅球颗粒细胞层中的神经母细胞和神经元减少。在体外，来自出生后脑室下区的 Ankrd11 缺陷神经干细胞表现出迁移、增殖和神经发生减少。最后，我们描述了两名临床和分子证实的 KBG 综合征患者，患有嗅觉丧失和嗅球和嗅沟发育不全/发育不全。我们的报告提供的证据表明 Ankrd11 是嗅球发育和神经母细胞迁移的新型调节剂。此外，我们的研究强调了与小鼠和人类 ANKRD11 扰动相关的 KBG 综合征的新临床症状。