Enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 ( Katnal2Δ 17 ) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular–subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2 Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2 Δ 17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.

中文翻译：

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自闭症基因 KATNAL2 的致病变异通过损害睫状微管动力学导致脑积水并破坏神经元连接


充满脑脊液 (CSF) 的脑室扩大（脑室扩大）是先天性脑积水 (CH) 的主要特征，在自闭症谱系障碍 (ASD) 患者中得到越来越多的认识。 KATNAL2 是 Katanin 家族微管切断 ATP 酶的成员，是已知的 ASD 风险基因，但其在人类大脑发育中的作用仍不清楚。在这里，我们发现小鼠中 Katnal2 ( Katnal2Δ 17 ) 的无义截短会导致典型的纤毛病表型，包括精子发生受损和脑室扩大。在人类和小鼠中，KATNAL2 在胎儿心室-心室下区的纤毛放射状胶质细胞及其出生后室管膜和神经元后代中高度表达。 Katnal2 Δ17 小鼠中观察到的脑室扩张与初级纤毛和室管膜平面细胞极性破坏有关，导致纤毛生成的脑脊液流动受损。此外，脑室扩大的 Katnal2 Δ 17 小鼠的前额锥体神经元表现出兴奋性驱动减少和高频放电减少。与小鼠中的这些发现一致，我们在 5 名接受神经外科治疗的 CH 并患有自闭症谱系障碍 (ASD) 或其他神经发育障碍的不相关患者中发现了 KATNAL2 中罕见的、破坏性的杂合种系变异。用与 ASD 相关的直向同源 KATNAL2 F244L 错义变体改造的小鼠重现了人类患者中发现的脑室扩大。总之，这些数据表明 KATNAL2 致病性变异通过破坏胎儿放射状胶质细胞及其出生后室管膜和神经元后代的微管动力学来改变脑室内 CSF 稳态和实质神经元连接。 这些结果确定了自闭症谱系障碍（ASD）患者遗传亚型中脑室扩大的分子机制，并可能解释了尽管进行了神经外科脑脊液分流，一些慢性CH患者神经发育表型的持续存在。