Hematological Disorders in Human Patients with Son Mutations
Authors: Vukadin Lana , Kim Jung-Hyun , Hackwelder Tara Bly , Ungerleider Nathan , Flemington Erik , Ahn Eun-Young Erin 
Published: November 2019

Precise regulation of transcription and RNA splicing is critical for controlling hematopoietic cell fate determination and lineage differentiation. Alteration of expression of lineage-specific transcription factors and several core spliceosome components in hematopoietic malignancies highlight the significance of abnormal transcription and RNA splicing as disease-causing factors. Our group previously demonstrated that SON, a large nuclear speckle protein possessing dual abilities to bind both DNA and RNA, functions as a splicing factor as well as a transcriptional repressor. We recently identified heterozygous loss-of-function mutations in the SON gene from children with intellectual disability and developmental delay often with a broad spectrum of other congenital anomalies. The disorder caused by SON haploinsufficiency has been designated as ZTTK syndrome (Zhu-Tokita-Takenouchi-Kim syndrome; OMIM #617140). The majority of the mutations found in these patients are frameshift or nonsense mutations which cause degradation of the mutation-bearing transcript. While the most prominent features of these patients are brain malformations and musculoskeletal abnormalities, we identified various hematological disorders from children with ZTTK syndrome. Notable symptoms include bone marrow failure, severe anemia, immunoglobulin deficiency, thalassemia, polycythemia, polycythemia vera, stroke due to blood clots, and leukocytopenia. Apart from the ZTTK syndrome, SON is known to be upregulated in acute myeloid leukemia (AML) patients and is correlated to altered hematopoietic differentiation. To investigate how altered SON expression affects hematopoiesis, we generated a mouse line with the Son gene deleted specifically in the hematopoietic lineage. Homozygous deletion of Son in hematopoietic lineage led to embryonic lethality, indicating that SON expression in blood cells is indispensable during development. Mice with heterozygous deletion of Son in the hematopoietic lineage were viable and born without notable defects or sign of diseases. However, there is a significant decrease in bone marrow cellularity in the mice with heterozygous deletion of Son. Furthermore, Son haploinsufficiency decreased the size of the lineage negative (Lin-) cell population and short-term hematopoietic stem cell (ST-HSC) population with a concurrent increase in megakaryocyte/erythrocyte lineage-biased multipotent progenitors (MPP2) within hematopoietic stem/progenitor cells. These findings suggest that the level of Son expression potentially affects stem cell maintenance and MPP lineage bias, and the distortion of the subpopulation balance within hematopoietic stem/progenitors is possibly linked to multiple hematological disorders. Our ongoing analyses of hematopoiesis and gene expression changes using this mouse model will expand our knowledge about the role of SON in several hematological disorders and benefit clinical practice for ZTTK syndrome patients.

Disclosures

No relevant conflicts of interest to declare.