A missense mutation in Katnal1 underlies behavioural, neurological and ciliary anomalies

作者：Banks G; Lassi G; Hoerder Suabedissen A; Tinarelli F; Simon M M; Wilcox A; Lau P; Lawson T N; Johnson S; Rutman A; Sweeting M; Chesham J E; Barnard A R; Horner N; Westerberg H; Smith L B; Molnar Z; Hastings M H; Hirst R A; Tucci V; Nolan P M^*

来源：Molecular Psychiatry, 2018, 23(3): 713-722.

DOI：10.1038/mp.2017.54

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.

• 出版日期2018-3