Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics.
Tyrone DeSpenzaAmrita SinghGarrett AllingtonShujuan ZhaoJunghoon LeeEmre KiziltugMackenzi L PrinaNicole DesmetHuy Q DangJennifer FieldsCarol Nelson-WilliamsJunhui ZhangKedous Y MekbibEvan DennisNeel H MehtaPhan Q DuyHermela ShimelisLauren K WalshArnaud MarlierEngin DenizEvelyn M R LakeR Todd ConstableEllen J HoffmanRichard P LiftonAllan T GulledgeSteven N FieringAndres Moreno-De-LucaShozeb M HaiderSeth L AlperSheng Chih JinKristopher T KahleBryan W LuikartPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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.
Keyphrases
- autism spectrum disorder
- cerebrospinal fluid
- high fat diet induced
- intellectual disability
- copy number
- high frequency
- resting state
- subarachnoid hemorrhage
- cerebral ischemia
- attention deficit hyperactivity disorder
- functional connectivity
- heart failure
- end stage renal disease
- endothelial cells
- genome wide
- white matter
- transcranial magnetic stimulation
- chronic kidney disease
- insulin resistance
- metabolic syndrome
- preterm infants
- ejection fraction
- spinal cord
- type diabetes
- early onset
- dna methylation
- congenital heart disease
- newly diagnosed
- room temperature
- left ventricular
- wild type
- oxidative stress
- cell therapy
- transcription factor
- patient reported