Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics

• 成果类型: Article
• 署名作者: DeSpenza Jr, Tyrone; Singh, Amrita; Allington, Garrett; Zhao, Shujuan; Lee, Junghoon; Kiziltug, Emre; Prina, Mackenzi L.; Desmet, Nicole; Dang, Huy Q.; Fields, Jennifer; Nelson-Williams, Carol; Zhang, Junhui; Mekbib, Kedous Y.; Dennis, Evan; Mehta, Neel H.; Duy, Phan Q.; Shimelis, Hermela; Walsh, Lauren K.; Marlier, Arnaud; Deniz, Engin; Lake, Evelyn M. R.; Constable, R. Todd; Hoffman, Ellen J.; Lifton, Richard P.; Gulledge, Allan; Fiering, Steven; Moreno-De-Luca, Andres; Haider, Shozeb; Alper, Seth L.; Jin, Sheng Chih; Kahle, Kristopher T.; Luikart, Bryan W.
• 署名单位: Yale University; Yale University; Yale University; Yale University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard Medical School; Washington University (WUSTL); Dartmouth College; Dartmouth College; Yale University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12811
• DOI: 10.1073/pnas.2314702121
• 发表日期: 2024-07-02
• 关键词: planar cell polarity; radial glial-cells; brain-development; ependymal cells; primary cilium; mutations; disorder; tracking; CHILDREN; cns

摘要

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 ( Katnal2 Delta 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 Delta 17 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 Delta 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.