ACTN1 was first reported in relation to autosomal dominant platelet-type bleeding disorder 15 in 2013 (Kunishima et al., PMID: 23434115). Affected individuals have macrothrombocytopenia and usually have no or only mild bleeding tendency, such as epistaxis. At least 27 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 30 probands in 8 publications (PMIDs: 23434115, 25361813, 26453073, 28562514, 27479822, 24069336, 31064749, 31237726). Variants in this gene segregated with disease in 65 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by functional alteration in patient (PMID: 25361813) and non-patient cells (PMID: 23434115). It is hypothesized that ACTN1 variants induce more stable actin filaments, thereby impairing stretching and leading to shorter and thicker fibers, however the reason why this mild phenotype is limited to platelets while ACTN1 has a ubiquitous expression is currently not well understood. In summary, ACTN1 is definitively associated with autosomal dominant platelet-type bleeding disorder 15.
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