LAUSR

In this issue of the British Journal of Haematology, Kawankar et al. report the results of a study where highthroughput exome sequencing and genomic bioinformatics analysis identified patients homozygous for two known and six novel variants in the RAS guanylreleasing protein 2 gene (RASGRP2). The cohort of mostly young Indian patients shared a history of mucosal bleeding, normal coagulation test results and platelet counts, and markedly depressed platelet response to adenosine diphosphate (ADP) and collagen under light transmission aggregometry (LTA). These findings parallel those of Canault et al. in 2014, which reported severe earlyonset bleeding in siblings homozygous for the c.G742T RASGRP2 variant, resulting in a p.G248W alteration from wildtype in RASGRP2, also known as calcium and diacylglycerolregulated guanine nucleotide exchange factor I (CalDAGGEFI). Subsequent studies identified patients with similar symptoms who were homozygous 5 or compound heterozygous for rare variants in RASGRP2. The LTA results from these patients parallel Glanzmann thrombasthenia (GT), where platelets have quantitative or qualitative deficiencies of the fibrinogen receptor, αIIbβ3, an integrin encoded by the ITGA2B and ITGB3 genes. Thus, it is not surprising that GT was the initial clinical diagnosis for several patients subsequently revealed to harbour rare variants in RASGRP2. This highlights the utility of modern genetic analysis in the diagnosis of patients suspected of having an inherited platelet disorder, particularly when platelet counts and morphology appear normal. Studies of RASGRP2 expression and function preceded the linking of this protein to human bleeding problems, as covered in a recent comprehensive review. Canonical RASGRP2 is a 609 amino acid protein (~69 kDa) expressed in several haematopoietic cell lineages, including platelets and precursor megakaryocytes. Like other members of its protein family RASGRP2 is a guanine exchange factor (GEF), although unlike other RASGRPs it exclusively activates Rap GTPases — the most abundant in the platelet lineage being functionally redundant Rap1A and Rap1B. Studies of RASGRP2 function in platelets have relied on Rasgrp2 mice, and revealed essential roles of this protein in several signalling pathways involved in the platelet activation response, including integrinmediated ‘insideout’ activation. The relevance of Rasgrp2 mice as a model for human RASGRP2 deficiency is strong, because studies where expression levels were examined have reported greatly reduced or absent platelet RASGRP2 in patients homozygous for c.914G>A (p.G305D), c.706C>T (p.Q236X), c.887G>A (p.C296Y), c.1142C>T (p.S321F) and c.337C>T (p.R113X), and also for those compound heterozygous for c.1178A>T (p.K360X) and c.1331_1333delCTG (p.L360del). Other reported variants are predicted to yield little or no functional protein, such as c.163A>T (p.L55X). However, as might be expected for a protein with multiple effects, not all pathogenic RASGRP2 variants depress expression. Notably, Canault et al. reported normal levels of RASGRP2 mRNA and protein in platelets from patients homozygous for the c.G742T (p.G248W) variant. Their Received: 21 January 2022 | Accepted: 24 January 2022