Uncovering phenotypic expansion in AXIN2-related disorders through precision animal modeling.
Обработка статьи · этапы, ошибки и управление
Ошибки и ограничения
История · было → стало
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Aceves-Ewing Nathalie M, Lanza Denise G, Marcogliese Paul C, Lu Di, Hsu Chih-Wei, Hashimoto Hirokazu, Gonzalez Matthew, Christiansen Audrey E, Rasmussen Tara L, Ho Alex J, Gaspero Angelina, Sha Cher, Dickinson Mary E, Yuan Bo, Shayota Brian J, Pachter Stephanie, Hu Xiaolin, Day-Salvatore Debra Lynn, Mackay Laura, Kanca Oguz, Wangler Michael F, Potocki Lorraine, Rosenfeld Jill A, Lewis Richard Alan, Chao Hsiao-Tuan, Lee Brendan, Blieden Lauren, Wasserman Barry N, Bax Dorine A, Ragge Nicola K, Lee Sukyeong, Undiagnosed Diseases Network, Baylor College of Medicine Center for Precision Medicine Models, Yamamoto Shinya, Bellen Hugo J, Burrage Lindsay C, Heaney Jason D
Аннотация
METHODS: Structural modeling was performed to predict the impact of these variants on AXIN2. A prime editing N1 screen of mouse embryos was performed to test whether the p.Glu66Lys variant produces a phenotype. Drosophila models were used to test the effect of this variant on Wnt signaling.
RESULTS: Structural modeling suggests that these variants disrupt AXIN2 binding to tankyrase, which regulates AXIN2 levels through poly-ADP-ribosylation. Heterozygous (p.Glu66Lys) mouse embryos were perinatally lethal with soft palate clefts and skeletal abnormalities. Modeling of the p.Glu66Lys variant in the Drosophila wing suggests gain-of-function or dominant-negative activity compared to reference AXIN2.
CONCLUSION: Specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with potential context-dependent effects on AXIN2 function and Wnt signaling. The N1 modeling strategy used to demonstrate variant pathogenicity may be beneficial for resolving other heterozygous variants associated with congenital anomalies.