Gray platelet syndrome (GPS) is an inherited bleeding disorder associated with 
macrothrombocytopenia and α-granule-deficient platelets. GPS has been linked to 
loss of function mutations in NEABL2 (neurobeachin-like 2), and we describe here 
a murine GPS model, the Nbeal2(-/-) mouse. As in GPS, Nbeal2(-/-) mice exhibit 
splenomegaly, macrothrombocytopenia, and a deficiency of platelet α-granules and 
their cargo, including von Willebrand factor (VWF), thrombospondin-1, and 
platelet factor 4. The platelet α-granule membrane protein P-selectin is 
expressed at 48% of wild-type levels and externalized upon platelet activation. 
The presence of P-selectin and normal levels of VPS33B and VPS16B in Nbeal2(-/-) 
platelets suggests that NBEAL2 acts independently of VPS33B/VPS16B at a later 
stage of α-granule biogenesis. Impaired Nbeal2(-/-) platelet function was shown 
by flow cytometry, platelet aggregometry, bleeding assays, and intravital 
imaging of laser-induced arterial thrombus formation. Microscopic analysis 
detected marked abnormalities in Nbeal2(-/-) bone marrow megakaryocytes, which 
when cultured showed delayed maturation, decreased survival, decreased ploidy, 
and developmental abnormalities, including abnormal extracellular distribution 
of VWF. Our results confirm that α-granule secretion plays a significant role in 
platelet function, and they also indicate that abnormal α-granule formation in 
Nbeal2(-/-) mice has deleterious effects on megakaryocyte survival, development, 
and platelet production.