Fountain M D, Tao H, Chen C-A, Yin J, Schaaf C P
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Genes Brain Behav. 2017 Jul;16(6):592-600. doi: 10.1111/gbb.12378. Epub 2017 Apr 4.
MAGEL2 is one of five protein-coding, maternally imprinted, paternally expressed genes in the Prader-Willi syndrome (PWS)-critical domain on chromosome 15q11-q13. Truncating pathogenic variants of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. 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 wild-type (WT) 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, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT 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 SHFYNG and PWS in general.
MAGEL2是位于15号染色体q11 - q13区域普拉德-威利综合征（PWS）关键区域的五个蛋白质编码、母源印记、父源表达的基因之一。MAGEL2的截短致病性变异会导致 Schaaf-Yang综合征（SHFYNG）（OMIM #615547），这是一种与PWS相关的神经发育障碍。受影响个体表现出一系列神经认知和行为表型，包括智力残疾和自闭症谱系障碍（ASD）。携带母源遗传的印记野生型（WT）等位基因和父源遗传的Magel2 - lacZ敲入等位基因（该等位基因消除了内源性Magel2基因功能）的Magel2基因敲除小鼠表现出一些让人联想到人类普拉德-威利表型的特征，包括新生儿生长迟缓、断奶后体重过度增加以及成年后肥胖增加。它们还表现出昼夜节律改变、运动活动减少和生育力降低。鉴于人类患者中ASD的高患病率，对该小鼠模型进行自闭症样行为的广泛评估是有必要的。通过旷场试验、高架十字迷宫试验、管状试验、三室试验和分隔试验对Magel2基因敲除小鼠及其野生型同窝小鼠的行为进行了测定。我们的研究证实，在旷场试验中，雄性和雌性小鼠的水平活动减少，雌性小鼠的垂直活动增加。在高架十字迷宫试验中，两性在开放臂中停留的时间都更长，这表明焦虑程度降低。在分隔试验中，两性对社交新奇性均缺乏偏好，即对已知和新伙伴缺乏区分能力。对Magel2功能丧失所导致的行为特征进行深入研究，有助于阐明SHFYNG和一般PWS行为表型的病因。
