De novo loss-of-function (LoF) variants in the KATNAL2 gene were identified in autistic probands from simplex families in two separate reports (PMIDs 22495306 and 22495309). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified KATNAL2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). A third de novo loss-of-function variant and a likely damaging de novo missense variant in KATNAL2 were identified in probands from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017 (PMID 28191889).
Molecular Function
Severs microtubules in vitro in an ATP-dependent manner. This activity may promote rapid reorganization of cellular microtubule arrays
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Katnal2 is strongly linked to ASD, and the mouse knockout model shows an increase in the volume of lateral ventricles, as well as increased ultrasonic vocalizations in adult male mice in response to female mice. These phenotypes are restored with reinstatement of Katnal2 expression.
References
Type
Title
Author, Year
Primary
Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
In the Katnal2 knockout allele (MGI:4842422) the critical exon 3 has been deleted. In the homozygous model this results in no protein expression of the Katnal2 gene.
Allele Type: Knockout
Strain of Origin: C57BL/6N-A^tm1Brd
Genetic Background: C57BL/6J
ES Cell Line: JM8A3.N1
Mutant ES Cell Line: Model Source: EUCOMM
Description: Magnetic resonance imaging (MRI) analysis revealed similar ventricular enlargements in the volumes of lateral ventricles among knockout mice (3 months). In contrast, the intracranial volumes of mutant mice (encompassing all ventricular and non-ventricular brain regions) remained largely unchanged, with very moderate increases in select brain regions.
Description: Pronounced ventricular enlargements in the two lateral ventricles of knockout brains were observed at P28 and P70. Some mutant mice (<10%) showed visually detectable macrocephaly with abnormal head shapes at approximately P28 and tended to die at approximately P30â??40. Total brain areas in coronal slices were moderately increased at P70 but not at P28 in knockout mice. At P7, lateral ventricular enlargements were moderate compared with those at P28 and P70.
Description: The flow rates of CSF in the cerebral aqueduct, which links the third and fourth ventricles, was increased in the brains of anesthetized knockout mice, as measured by MRI.
Description: Cerebral blood volume-weighted signals, measured by T2*-weighted single-shot gradient-echo echo-planar images (GE-EPI) combined with acute hypoxic nitrogen stimulus, were decreased in various brain regions, including the hippocampus.
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Increased
Description: Male knockout mice emit courtship USVs of increased frequency and duration upon encounter with a female stranger mouse compared to male wildtype mice.
Description: Knockout mice show differential gene expression at 3 and 10 weeks of age (28 up- and 11 down-regulated at P21, and 81 up- and 66 down-regulated at P70).
