Genetic and molecular basis of hematopoietic abnormalities in ZTTK syndrome

PROJECT SUMMARY
Individuals with rare genetic diseases do not receive attention from the medical and research community. One
out of two patients diagnosed with a rare disease is a child, meaning that patients and their families must endure
long battles relating to disease progress throughout their child’s lifetime. Therefore, characterization of
clinical/molecular aspects of rare diseases will greatly benefit young patients and their families.
SON is a DNA- and RNA-binding protein that plays dual roles as an RNA splicing factor and a transcriptional
repressor. Our research team recently identified Zhu-Tokita-Takenouchi-Kim syndrome (ZTTK syndrome), a
rare genetic disease with multi-organ abnormalities caused by heterozygous loss-of-function mutations in the
SON gene (SON haploinsufficiency). Our research and publication played a key role in documenting this
syndrome in major public databases to facilitate clinical diagnosis. As a first step in supporting ZTTK families
and promoting awareness, we recently launched an official foundation, the ZTTK SON-Shine Foundation.
Our recent efforts revealed that many children with ZTTK syndrome experience various hematopoietic disorders
and immune dysfunction, which sometimes leads to life-threatening sepsis. To understand the hematopoietic
abnormalities associated with ZTTK syndrome, we have generated mouse models of Son knockout (KO) and
Son haploinsufficiency. Our preliminary data demonstrated that complete Son KO in hematopoietic cells causes
hematopoietic stem cell (HSC) expansion and embryonic lethality. Furthermore, we found that Son
haploinsufficiency leads to abnormal proportions of lineage-primed multipotent progenitors (MPPs), with an
expansion of megakaryocyte-erythroid lineage-primed MPPs and a shrinkage of lymphoid lineage-primed MPPs,
which is already evident during fetal liver hematopoiesis and persists in adult hematopoiesis in the bone marrow.
Importantly, our RNA-sequencing analyses revealed that critical chromatin modifier genes were the major targets
dysregulated by Son haploinsufficiency in early stage hematopoietic stem and progenitor cells (HSPCs).
Based on these preliminary data, our central hypothesis is that Son haploinsufficiency directly and indirectly
alters the expression/splicing of key chromatin modifiers, which collectively reshapes chromatin status at the
level of HSCs and MPPs, and this leads to skewed lineage bias and impaired functional output of HSCs/MPPs.
To test these hypotheses, we will investigate how Son haploinsufficiency affects functional output of HSCs and
lineage primed MPPs in vivo (Aim 1), and will dissect the underlying molecular mechanisms by which Son
haploinsufficiency leads to HSPC abnormalities (Aim 2). Successful completion of this proposed study will
significantly advance our knowledge about ZTTK syndrome-associated abnormal hematological features and
will serve as a valuable resource to identify therapeutic strategies. Most importantly, this study will bring hope to
children and their families battling this rare disease.

Grant Number: 5R01HL168659-03
NIH Institute/Center: NIH
Principal Investigator: Erin Ahn