title: A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies.
abstract: Microtubule severing enzymes implement a diverse range of tissue-specific molecular functions throughout development and into adulthood. Although microtubule severing is fundamental to many dynamic neural processes, little is known regarding the role of the family member Katanin p60 subunit A-like 1, KATNAL1, in central nervous system (CNS) function. Recent studies reporting that microdeletions incorporating the KATNAL1 locus in humans result in intellectual disability and microcephaly suggest that KATNAL1 may play a prominent role in the CNS; however, such associations lack the functional data required to highlight potential mechanisms which link the gene to disease symptoms. Here we identify and characterise a mouse line carrying a loss of function allele in Katnal1. We show that mutants express behavioural deficits including in circadian rhythms, sleep, anxiety and learning/memory. Furthermore, in the brains of Katnal1 mutant mice we reveal numerous morphological abnormalities and defects in neuronal migration and morphology. Furthermore we demonstrate defects in the motile cilia of the ventricular ependymal cells of mutants, suggesting a role for Katnal1 in the development of ciliary function. We believe the data we present here are the first to associate KATNAL1 with such phenotypes, demonstrating that the protein plays keys roles in a number of processes integral to the development of neuronal function and behaviour.
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: G
authors.initials: G
authors.lastname: Banks
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Lassi
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: A
authors.initials: A
authors.lastname: Hoerder-Suabedissen
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Tinarelli
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Simon
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: A
authors.initials: A
authors.lastname: Wilcox
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: P
authors.initials: P
authors.lastname: Lau
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: T N
authors.initials: TN
authors.lastname: Lawson
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: S
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RK Clinical Sciences Building, University of Leicester, Leicester, UK.
authors.forename: A
authors.initials: A
authors.lastname: Rutman
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: M
authors.initials: M
authors.lastname: Sweeting
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: J E
authors.initials: JE
authors.lastname: Chesham
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Barnard
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: N
authors.initials: N
authors.lastname: Horner
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: H
authors.initials: H
authors.lastname: Westerberg
authors.affiliation: MRC Centre for Reproductive Health, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: L B
authors.initials: LB
authors.lastname: Smith
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Molnár
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Hastings
authors.affiliation: Centre for PCD Diagnosis and Research, Department of Infection, Immunity and Inflammation, RK Clinical Sciences Building, University of Leicester, Leicester, UK.
authors.forename: R A
authors.initials: RA
authors.lastname: Hirst
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Tucci
authors.affiliation: MRC Harwell Institute, Harwell Science and Innovation Campus, Didcot, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Nolan
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002923:Cilia / Q000235:genetics / Q000502:physiology; D002940:Circadian Rhythm / Q000235:genetics; D004805:Ependyma / Q000378:metabolism; D006801:Humans; D000074201:Katanin / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008831:Microcephaly; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012890:Sleep / Q000235:genetics
chemical_list: D000251:Adenosine Triphosphatases; C000600349:KATNAL1 protein, human; D000074201:Katanin; C552938:Katna1 protein, mouse