Biallelic deleterious germline SH2B3 variants cause a novel syndrome of myeloproliferation and multi-organ autoimmunity

Blombery, P; Pazhakh, V; Albuquerque, AS; Maimaris, J; Tu, L; Briones Miranda, B; Evans, F; Thompson, ER; Carpenter, B; Proctor, I; Curtin, JA; Lambert, J; Burns, SO; Lieschke, GJ

Author(s): Blombery, P; Pazhakh, V; Albuquerque, AS; Maimaris, J; Tu, L; Briones Miranda, B; Evans, F; Thompson, ER; Carpenter, B; Proctor, I; Curtin, JA; Lambert, J; Burns, SO; Lieschke, GJ;
Details: Publication Year 2023-05,Volume 4,Issue #2,Page 463-469
Journal Title: eJHaem
Publication Type: Research article
Abstract: SH2B3 is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss-of-function SH2B3 variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss-of-function SH2B3 variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi-organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the sh2b3 crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin-derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL-3, GH, GM-CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants in SH2B3 to be considered a valid gene-disease association for a clinical syndrome of bone marrow myeloproliferation and multi-organ autoimmune manifestations.
Publisher: Wiley
Keywords: genetics; molecular diagnosis; myeloid function and development
Department(s): Clinical Haematology
PubMed ID: 37206266
Publisher's Version: https://doi.org/10.1002/jha2.698
Open Access at Publisher's Site: https://doi.org/10.1002/jha2.698
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-08 01:31:22

Last Modified: 2023-08-08 01:31:53