2024
Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics
DeSpenza T, Singh A, Allington G, Zhao S, Lee J, Kiziltug E, Prina M, Desmet N, Dang H, Fields J, Nelson-Williams C, Zhang J, Mekbib K, Dennis E, Mehta N, Duy P, Shimelis H, Walsh L, Marlier A, Deniz E, Lake E, Constable R, Hoffman E, Lifton R, Gulledge A, Fiering S, Moreno-De-Luca A, Haider S, Alper S, Jin S, Kahle K, Luikart B. Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics. Proceedings Of The National Academy Of Sciences Of The United States Of America 2024, 121: e2314702121. PMID: 38916997, PMCID: PMC11228466, DOI: 10.1073/pnas.2314702121.Peer-Reviewed Original ResearchConceptsCongenital hydrocephalusCerebral ventriculomegalyPathogenic variantsPrefrontal pyramidal neuronsGenetic subsets of patientsDevelopment of ventriculomegalyRadial gliaSubsets of patientsHigh-frequency firingNeuronal connectivityHeterozygous germline variantsAutism spectrum disorderVentricular-subventricular zoneMicrotubule dynamicsImpaired spermatogenesisCSF shuntingExcitatory driveMicrotubule-severing ATPasePyramidal neuronsDisrupt neuronal connectivityGermline variantsVentriculomegalyCSF homeostasisDisrupt microtubule dynamicsPlanar cell polarity184 PTEN Mutations Portend Cerebral Ventriculomegaly With Autism-Like Deficits in Cortical Circuitry
DeSpenza T, Kizlitug E, Allington G, Barson D, O'Connor D, Robert S, Mekbib K, Singh A, Phan D, Nanda P, Mandino F, Constable T, Lake E, Carter B, Gunel M, Lifton R, Luikart B, Kahle K. 184 PTEN Mutations Portend Cerebral Ventriculomegaly With Autism-Like Deficits in Cortical Circuitry. Neurosurgery 2024, 70: 46-46. DOI: 10.1227/neu.0000000000002809_184.Peer-Reviewed Original ResearchWhole-exome sequencingFetal ventriculomegalyCongenital hydrocephalusExome sequencingChoroid plexus hyperplasiaMutated genesCa2+ imagingMutant mouse modelsPTEN mutantsHuman fetal brainPten mutant miceSporadic CHCerebral ventriculomegalyCSF diversionObstructive hydrocephalusCH patientsCSF secretionPharmacological mTORC1 inhibitionNeurodevelopmental assessmentRadiographic biomarkersFetal brainPTEN mutationsAqueductal stenosisPTEN deletionVentriculomegaly
2023
A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus
Singh A, Allington G, Viviano S, McGee S, Kiziltug E, Ma S, Zhao S, Mekbib K, Shohfi J, Duy P, DeSpenza T, Furey C, Reeves B, Smith H, Sousa A, Cherskov A, Allocco A, Nelson-Williams C, Haider S, Rizvi S, Alper S, Sestan N, Shimelis H, Walsh L, Lifton R, Moreno-De-Luca A, Jin S, Kruszka P, Deniz E, Kahle K. A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus. Brain 2023, 147: 1553-1570. PMID: 38128548, PMCID: PMC10994532, DOI: 10.1093/brain/awad405.Peer-Reviewed Original ResearchAqueductal stenosisDe novo variantsCardiac defectsCerebral ventriculomegalyPatient cohortFetal brain transcriptomeStructural brain disordersTranscription factor NeuroD2Large patient cohortCorpus callosum abnormalitiesHuman fetal brainOptical coherence tomographyWhole-exome sequencingNeural stem cellsCH patientsHuman hydrocephalusControl cohortClinical managementCommon disorderCallosum abnormalitiesFetal brainBrain disordersBrain surgeryCH pathogenesisPatients