Germline heterozygous SH2B3-mutations and (idiopathic) erythrocytosis: Detection of a previously undescribed mutation

Abstract

Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with "idiopathic erythrocytosis" (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK-STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work-up.

Keywords: erythrocytosis; idiopathic erythrocytosis; myeloid function and development; myeloproliferative disorder.

FIGURE 1

Graphical representation of SH2B3 and the interaction with JAK‐STAT. (A) The SH2B adaptor protein 3 gene, located on chromosome 12, codes for the lymphocyte adaptor protein (LNK), also known as SH2B3. This adaptor family also contains SH2B1 and SH2B3. The Src homology 2 (SH2) domain‐containing adaptor family shows the same protein architecture, existing out of an N‐terminal dimerization domain (DD), pleckstrin homology domain (PH) and a C‐terminal SH2 domain. (B) LNK may directly inhibit the Janus Kinase‐signal transducer and activator of transcription (JAK‐STAT) signaling pathway. Other interacting proteins (semi‐transparent color) such as phosphatases and suppressor of cytokine signaling (SOCS) are not discussed in this article. (Figure extracted from: Morris R, Butler L, Perkins A, Kershaw NJ, Babon JJ. The role of lnk (Sh2b3) in the regulation of jak‐stat signaling in haematopoiesis. Pharmaceuticals 2022;15. https://doi.org/10.3390/ph15010024).