A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis

• DOI: 10.1172/jci.insight.175053
• Publication Date: 2024-01-30T21:01:17Z
• Authors: Lana Vukadin; Bohye Park; Mostafa Mohamed; Huashi Li; Amr Elkholy; Alex Torrelli-Dil...; Jung-Hyun Kim; Kyuho Jeong; James M. Murphy; Caitlin A. Harvey; Sophia Dunlap; Leah Gehrs; Hanna Lee; Hyung-Gyoon Kim; Jay Prakash Sah; Seth N. Lee; Denise Stanford; Robert A. Barrington; Jeremy B. Foote; Anna G. Sorace; Robert S. Welner; Blake E. Hildreth...; Ssang-Taek Steve Lim; Eun-Young Erin Ahn
• Keywords: Haploinsufficiency; Lymphopoiesis

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result heterozygous loss-of-function of SON. While ZTTK patients suffer from numerous symptoms, the lack model organisms hampers our understanding SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/−) mice as identified indispensable roles organ development hematopoiesis. Son+/− recapitulated clinical symptoms syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, kidney agenesis. Furthermore, hematopoietic abnormalities mice, leukopenia immunoglobulin deficiency, similar those observed human patients. Surface marker analyses single-cell transcriptome profiling stem progenitor cells revealed shifts cell fate more toward myeloid lineage but compromises lymphoid reducing genes required for B-cell specification. Additionally, causes inappropriate activation erythroid impaired erythropoiesis. These findings highlight importance full gene expression multiple organs. Our serves an invaluable research tool related disorders associated with dysfunction.