This week, we profile a recent publication in the Journal of Experimental Medicine from Eric Allenspach (pictured) at Seattle Children’s.
Can you provide a brief overview of your lab’s current research focus?
My lab focuses on understanding genetic variation that causes immune system dysregulation. We focus on human genetic changes that lead to both increased infection as well as autoimmune disease. Variants can be found to be spontaneous (de novo) or can run in families or even populations. The goal is to understand both rare and common genetic variation in an effort to provide precision medicine and better-targeted therapies.
What is the significance of the findings in this publication?
The recent publication in the Journal of Experimental Medicine is about a rare case of SAMD9L-associated autoinflammatory disease but has broader implications for bone marrow failure disorders and myeloid malignancies. SAMD9L is one of our interferon-stimulated genes involved in the immune system’s early anti-viral response. Typically a targeted block in protein synthesis can help hinder a virus, but a global block in translation leads to bone marrow failure and disease features found in this disease. Together with my collaborators, we found that when SAMD9L is truncated or shortened to a critical length the protein becomes overactive (or gain-of-function) causing a profound translational block. Clinically this results in bone marrow failure with anemia, low platelets, and low lymphocyte counts, while an escape mechanism for those arrested cells is loss of the mutant allele resulting in monosomy 7, a known association with myeloid cancers. We hope this manuscript leads to more awareness of this condition as early diagnosis is critical for considering hematopoietic stem cell transplantation, which has been a successful therapy in some patients.
This work was funded by:
The above observation led us to apply and receive grant funding from the Brotman Baty Institute for Precision Medicine. The grant aim is to perform a deep mutational scan of this region to further define genetic variants and truncations that lead to a similar gain-of-function translational block and which variants are rather loss-of-function. The goal is to define all possible genetic variants in this gene prior to patients presenting with this aggressive disease. We also will be exploring the role of SAMD9L in regulating the antiviral response.
