Page 12 - K. Development and regeneration

[K. Development and regeneration-9]

A novel de novo heterozygous dyrk1a mutation causes

complete loss of dyrk1a function and developmental delay

Miri Choi¹˙²˙#, Kyu-Sun Lee³˙⁴˙#, Dae-Woo Kwon³˙⁴˙#, Doyoun Kim⁵, Jong-Moon Choi⁶, Ae-Kyeong Kim³,
Youngwook Ham¹˙², Sang-Bae Han², Chong Kun Cheon⁸˙⁹˙*, Sungchan Cho¹˙⁷˙*

¹Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si 28116,
Republic of Korea, ²College of Pharmacy, Chungbuk National University, Cheongju-si 28644, Republic of Korea,
³Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141,

Republic of Korea, ⁴Department of Functional Genomics, KRIBB School of Bioscience, Daejeon 34113, Republic of
Korea, ⁵Innovative Target Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114,
Republic of Korea, ⁶Green Cross Genome, Green Cross Laboratories, Yongin-si 16924, Republic of Korea, ⁷
Department of Biomolecular Science, KRIBB School of Bioscience, Daejeon 34113, Republic of Korea, ⁸Division of
Medical Genetics and Metabolism, Pusan National University School of Medicine, Yangsan-si 50612, Republic of
Korea, ⁹Research Institute for Convergence of Biomedical Science and Technology, Pusan National University
Children’s Hospital, Yangsan-si 50612, Republic of Korea

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is essential in 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 defect 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 the C-terminally truncated protein. Analysis of the structure and deformation energy of the mutant
protein predicted a reduction in protein stability. Experimentally, the mutant protein was effectively 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 effect on the wild-type protein. Similarly, it had a

minimal effect on Drosophila phenotypes, confirming its loss-of-function in vivo. Our work indicates 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.