by Hannah Buckelew

Erin Eun-Young Ahn, Ph.D., an associate professor in the UAB Department of Pathology’s Division of Molecular and Cellular Pathology, was recently awarded an R01 from the National Institute of Health’s (NIH) National Heart, Lung, and Blood Institute for the project titled, “Genetic and molecular basis of hematopoietic abnormalities in ZTTK syndrome.” The grant, funded for $2 million, began March 15, 2023, and will run through December 31, 2026.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease primarily identified in children that is characterized by intellectual disability, delayed motor-psycho development and multi-organ anomalies, and is caused by loss-of-function mutations in the SON gene (SON haploinsufficiency.) The SON gene creates a DNA and RNA binding protein, SON, that is required for the body to grow and develop naturally.

Since the early 2000s, Ahn has been studying the SON protein and gene. Her work led to the discovery of ZTTK in 2016, and to the establishment of the SON-Shine Foundation in 2020 to provide a community of support among newly diagnosed patients and their families. In late 2021, Ahn was named a UAB Heersink School of Medicine Featured Discovery winner for an additional study on RNA splicing and SON.

“This grant continues the story of the discovery of the ZTTK syndrome,” Ahn says.

Ahn’s recent studies have revealed that many children diagnosed with ZTTK syndrome experience hematopoietic disorders and immune dysfunction which may lead to life-threatening sepsis. Hematopoietic stem cells (HSC) are immature cells that can develop into all blood cell types, such as red blood cells, white blood cells and platelets, to create a balanced number of cell types. Ahn suspects, however, that ZTTK patients’ HSC are causing an imbalance in cell lineage.

“We think there is a defect in the hematopoietic stage in that it’s creating more myeloid cells and red blood cells while generating less lymphoid cells, but all with immature properties,” Ahn says. “If these cells are being stopped in the middle of their maturation process, then they would not be able to function as blood cells to support and protect our body.”

Ahn’s team aims to delineate the mechanism underlying hematopoietic abnormalities in ZTTK syndrome. She hypothesizes that SON haploinsufficiency alters the expression and splicing of key chromatin modifiers, which leads to skewed cell lineage and impaired functional output. Her research team will employ novel mouse models and custom bioinformatics tools to examine how SON haploinsufficiency affects the function of HSC and lineage primed multipotent progenitors in vivo, and dissect the underlying molecular mechanisms by which SON haploinsufficiency leads to HSC abnormalities.

Co-investigators with Ahn on this grant include Christopher Klug, Ph.D., UAB Department of Microbiology, Robert Welner, Ph.D., Division of Hematology/Oncology, UAB Department of Medicine, and Xinyang Zhao, Ph.D., Department of Pathology and Laboratory Medicine at the University of Kansas Medical Center.

“The knowledge from this study will serve as valuable resources in identifying potential therapeutic strategies,” Ahn says. “We want to improve hematopoietic function and overall quality of life for children living with ZTTK and their families.”