Platelet-type bleeding disorder-15 is an autosomal dominant form of macrothrombocytopenia. Affected individuals usually have no or only mild bleeding tendency, such as epistaxis. Laboratory studies show decreased numbers of large platelets and anisocytosis, but the platelets show no ... Platelet-type bleeding disorder-15 is an autosomal dominant form of macrothrombocytopenia. Affected individuals usually have no or only mild bleeding tendency, such as epistaxis. Laboratory studies show decreased numbers of large platelets and anisocytosis, but the platelets show no in vitro functional abnormalities (summary by Kunishima et al., 2013).
Kunishima et al. (2013) reported 11 individuals from 6 unrelated Japanese families with congenital macrothrombocytopenia. Affected individuals had about half-normal platelet counts and a 30% increase in platelet size. Peripheral blood smear showed anisocytosis. Electron microscopy showed no ... Kunishima et al. (2013) reported 11 individuals from 6 unrelated Japanese families with congenital macrothrombocytopenia. Affected individuals had about half-normal platelet counts and a 30% increase in platelet size. Peripheral blood smear showed anisocytosis. Electron microscopy showed no other abnormalities. Bleeding diathesis was absent or mild if present: only 2 individuals (15%) experienced occasional epistaxis, and the bleeding time was within the normal limit. In vitro studies showed no apparent defects in platelet functions, including normal platelet aggregation, clot retraction, and platelet spreading on glass surfaces.
In affected members of 6 unrelated Japanese families with autosomal dominant platelet-type bleeding disorder-15, Kunishima et al. (2013) identified 6 different heterozygous missense mutations in the ACTN1 gene (102575.0001-102575.0006). Three of the mutations were identified by exome sequencing. ... In affected members of 6 unrelated Japanese families with autosomal dominant platelet-type bleeding disorder-15, Kunishima et al. (2013) identified 6 different heterozygous missense mutations in the ACTN1 gene (102575.0001-102575.0006). Three of the mutations were identified by exome sequencing. ACTN1 mutations were found in 5.5% of the dominant forms of congenital macrothrombocytopenia in their cohort, and represented the fourth most common cause of the disorder in Japanese individuals. Expression of the mutations in Chinese hamster ovary (CHO) cells showed that the mutant proteins caused varying degrees of disorganization of the actin filaments, with mutant ACTN1 colocalized with less fine, shortened actin filaments, and unbound ACTN1 coarsely distributed within the cytoplasm. Expression of 2 of the mutations (V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived megakaryocytes resulted in less organization of the circumferential actin-filament network compared to controls. The findings suggested that ACTN1 mutations dominantly affected the actin filament assembly, likely resulting in abnormal cytoskeletal organization. Examination of proplatelet formation from megakaryocytes showed that the G32K and V105I mutations did not change the rate of proplatelet formation or platelet production, but did reduce the number of proplatelet tips and increase the size of proplatelet tips from megakaryocytes.