The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia

Abstract

The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)—accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.

Differentially expressed platelet activation-related genes in dogs with stage B2 myxomatous mitral valve disease

“…Importantly, RhoA GTPases are master orchestrators of platelet physiology by inducing the vascular effects of various vasoactive factors to promote hemostasis, and play a major role in the development of cardiovascular disease [ 50 , 51 ]. ROCK1/2 inhibition increased megakaryocytes ploidy, aberrant proplatelet release, and macrothrombocytopenia [ 52 – 54 ]. Interestingly, another study found that both macrothrombocytopenia and an increase in LV fractional shortening were associated with a more hypercoagulable hemostatic system in dogs with MMVD.…”

Actin Bundles Dynamics and Architecture

“…Similarly, as a scaffolding protein, α-actinin coordinates the organization of various actin-based structures, from sarcomeres to focal adhesions [ 84 ]. Mutations in α-actinin isoforms are linked to several human diseases, such as autosomal-dominant congenital macrothrombocytopenia [ 85 , 86 ], dilated or hypertrophic cardiomyopathy [ 87 ], familial focal segmental glomerulosclerosis (FFSG) [ 88 , 89 ], carcinomas [ 90 , 91 ], and immunological diseases [ 92 ].…”

“…Mutations in α-actinin-1 lead to focal segmental glomerulosclerosis [ 89 ] and congenital macrothrombocytopenia [ 97 , 98 ]. This correlates with the knock-down of this protein, preventing megakaryocyte polyploidization that is essential for platelet production [ 86 ]. Mutations in ACTN4, encoding α-actinin-4 that binds actin more strongly than the wild-type (WT) protein, cause familial focal segmental glomerulosclerosis [ 88 , 99 ].…”

“…These Z-repeats are ~45 a.a. long regions, and their number correlates with the number of α-actinin dimers bound to actin bundles in the Z-disks of various types of striated muscle [ 109 , 127 , 128 , 129 ]. At focal adhesions, α-actinin associates with zyxin, vinculin, and with cell surface receptors β-integrins [ 86 , 130 ]. PDZ- and LIM-domain protein CLP36 binding to α-actinin-1 shifts its localization from focal adhesions to stress fibers [ 131 ].…”

Platelet Storage Pool Disease in a Family with Thrombocytopenia and a Pathogenic Variant in the α-Actinin Encoding Gene ACTN1

“…Binding regions of the α-actin molecule dimerize into rod-like structures that allow for cross-linking of actin filaments into bundles. In cooperation with other cytoskeletal proteins, actin filaments play an important role in platelet morphology [3]. A disruption of actin filament cross-linking appears to disrupt cytoplasmic organization, according to electron microscopy and immunofluorescence studies of affected megakaryocytes [4].…”