[논문]A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay

Lee, Kyu-Sun; Choi, Miri; Kwon, Dae-Woo; Kim, Doyoun; Choi, Jong-Moon; Kim, Ae-Kyeong; Ham, Youngwook; Han, Sang-Bae; Cho, Sungchan; Cheon, Chong Kun

doi:10.1038/s41598-020-66750-y

[해외논문] A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay 원문보기

Scientific reports, v.10, 2020년, pp.9849 -

Lee, Kyu-Sun (Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea) , Choi, Miri (Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungbuk, 28116 Republic of Korea) , Kwon, Dae-Woo (Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea) , Kim, Doyoun (Innovative Target Research Center, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Jang-dong, Yuseong-gu, Daejeon, 34114 Republic of Korea) , Choi, Jong-Moon (Green Cross Genome, Green Cross Laboratories, 107 Ihyeon-ro 30 beon-gil, Giheung-gu, Yongin-si, Gyeonggi, 16924 Republic of Korea) , Kim, Ae-Kyeong (Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141 Republic of Korea) , Ham, Youngwook (Natural Medicine Research Center, Korea Research Institute) , Han, Sang-Bae , Cho, Sungchan , Cheon, Chong Kun

Abstract ▼ AI-Helper

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is essential for human development, and DYRK1A haploinsufficiency is associated with a recognizable developmental syndrome and variable clinical features. Here, we present a patient with DYRK1A haploinsufficiency syndrome, including facial dysmorphism, delayed motor development, cardiovascular system defects, and brain atrophy. Exome sequencing identified a novel de novo heterozygous mutation of the human DYRK1A gene (c.1185dup), which generated a translational termination codon and resulted in a C-terminally truncated protein (DYRK1A-E396ter). To study the molecular effect of this truncation, we generated mammalian cell and Drosophila models that recapitulated the DYRK1A protein truncation. Analysis of the structure and deformation energy of the mutant protein predicted a reduction in protein stability. Experimentally, the mutant protein was efficiently degraded by the ubiquitin-dependent proteasome pathway and was barely detectable in mammalian cells. More importantly, the mutant kinase was intrinsically inactive and had little negative impact on the wild-type protein. Similarly, the mutant protein had a minimal effect on Drosophila phenotypes, confirming its loss-of-function in vivo. Together, our results suggest that the novel heterozygous mutation of DYRK1A resulted in loss-of-function of the kinase activity of DYRK1A and may contribute to the developmental delay observed in the patient.

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