Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty

Abstract

MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (OMIM #615547), a neurodevelopmental disorder related to Prader-Willi syndrome. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wildtype allele and a paternally inherited Magel2-lacZ knock-in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader-Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning, and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity, and reduced fertility. An extensive assessment for autism-like behaviors in this mouse model was warranted, due to the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their wildtype littermates were assayed via open field, elevated plus maze, tube, three-chamber, and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in-depth investigation of behavioral profiles caused by Magel2 loss-of-function helps to elucidate the etiology of behavioral phenotypes both for Schaaf-Yang syndrome and Prader-Willi syndrome in general.

Genetic control of temperament traits across species: association of autism spectrum disorder risk genes with cattle temperament

“…The human genomic region (15q11-q13) that is orthologous to the top associated region in the flight time meta-analysis (start of bovine chromosome 21) encompasses genes that have been implicated in several behavioural and cognitive disorders, including childhood obesity [58], epilepsy [59] and the genetic disorders Angelman and Prader-Willi syndromes [60,61]. Mouse and rat models have shown that copy number variation in this region is involved in feeding disorders, delayed motor skills development, and altered circadian rhythm [62][63][64]. In cattle, variants in this region, located at the start of chromosome 21, are associated with aggressiveness [14] and fertility [65,66].…”

OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

“…Although we have observed a strong and cross-validated OTUD7A phenotype, our results indicate a multi-hit hypothesis where more than one gene contributes to the etiology of 15q13.3 microdeletion syndrome, which is in line with other CNVs. For example, DGCR8 and ZDHHC8 are proposed driver genes in the 22q11.2 microdeletion, UBE3A and MAGEL2 for the 15q11-13 microdeletion region, 73 , 74 and GTF2I and FZD9 for the 7q11.23 region. 75 , 76 , 77 For the 15q13.3 CNV, future experiments are needed using OTUD7A and CHRNA7 single and double KO cellular models to compare to the 15q13.3 microdeletion to determine the unique and shared contribution of each gene to disease pathogenesis.…”

Cellular and disease functions of the Prader–Willi Syndrome geneMAGEL2

“…In line with disrupted sleep-wake cycles in mice and patients, Magel2 knockout mice have decreased orexin level, accompanied by increase in prohormone prepro-orexin, suggesting a defect in the maturation process of the hormone (112). Magel2 knockout mice also have decreased levels of diverse neurotransmitters, including serotonin, dopamine and catecholaminergic biogenic amines in various regions of the brain (114, 118) and manifest several abnormal behaviors, such as an increase in anxiety in novel environment, altered social phenotypes, and a deficit in preference for social novelty (114, 118, 119). Notably, low central nervous system (CNS) serotonin levels have been associated with impulsive, aggressive and self-injurious behavior that is exemplified in PWS patients (120).…”