Two de novo damaging missense variants in KIRREL3 were identified in ASD probands from the Autism Seqeuncing Consortium (De Rubeis et al., 2014) and the Simons Simplex Collection (Iossifov et al., 2014). Additional variants in KIRREL3 have been identified in patients with related neurodevelopmental disorders (Bhalla et al., 2008; Talkowski et al., 2012).
The protein encoded by this gene is a member of the nephrin-like protein family. These proteins are expressed in fetal and adult brain, and also in podocytes of kidney glomeruli. Mutations in this gene are associated with mental retardation autosomal dominant type 4 (MRD4; OMIM 612581).
Type of Disorder
Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.
Kirrel3 null mice display preference for a mouse over a non-social object but no significant preference for a stranger mouse over a familiar mouse. Kirrel3 null mice show impaired ultrasonic communications, including pup-to-mother calls, male-female courtship vocalisation and resident responses to intruder. Kirrel3 mice show increased locomotor activity and repetitive rearing. Kirrel3 null mice show enhanced performance on the rotarod test. Kirrel3 null mice were significantly hypersensitive to acoustic stimuli. Kirrel3 null mice show no change in anxiety-related behaviors and spatial or fear memory acquisition (Hisaoka T, et al, Sci. Rep., 2018).
Abnormal behaviours relevant to neurodevelopmental disorders in Kirrel3-knockout mice.
Mice bearing a targeted null deletion of the entire coding region of Kirrel3 (The deleted part of the Kirrel3 gene includes the entire Kirrel3 coding region starting with the translation initiation codon in exon 1 and ending downstream of exon 16, the last exon). The targeting construct was designed to replace the Kirrel3 coding region with NLS-LacZ and the selection gene (PGK-Neo) bracketed by loxP recombination signals, which was later deleted by mating with mice expressing Cre recombinase. .
Allele Type: Knockout
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not specified
Mutant ES Cell Line: Not specified
Model Source: Ozgene Pty Ltd (Bentley DC, Australia)
Description: Mutants show greater motor activity in the light compartment compared to controls. Mutants show no change in motor activity in the dark compartment compared to controls. Mutants exhibit more transitions between the light and dark compartments than controls.
Description: Mutants require increased current of foot show to elicit vocalization response. Mutants show no change in current level to elicit flinching or jumping responses compared to controls.
Exp Paradigm: Flinching, vocalising, and jumping behaviours were measured.
Description: Mutants show lower aggressive behavior toward a same-sex and same-strain intruder compared to wildtype controls. When mutants did attack the intruding mouse, the attack duration was shorter in mutants compared to wildtype controls.
Exp Paradigm: Same sex C57BL/6J intruder mice were used.
Description: Mutants emit lower ultrasonic vocalization compared to controls.
Exp Paradigm: After an intruder mouse is introduced into a resident home cage, the resident mouse typically emits USVs to establish a social dominance.
Ultrasonic vocalization: interaction induced: opposite sex stimulus1
Description: Mutant male mice emit lower numbers of ultrasonic vocalizations to an oestrous female compared to wildtype controls.
Exp Paradigm: The number of ultrasonic calls during free interactions of a tested male mouse with an oestrous C57BL/6J female mouse was measured.
Description: Mutants show no expression of 100kDa Kirrel3 protein in the olfactory bulb, cerebral cortex and hippocampus, compared to controls.
Exp Paradigm: Beta-actin was used as the loading control.