Mitotic abnormalities and spindle assembly checkpoint inactivation in a cell model of Shwachman-Diamond syndrome with mutations in the Shwachman-Bodian-Diamond syndrome gene, 258+2T > C

Hematologic abnormalities are the most common symptoms of Shwachman-Diamond syndrome (SDS). The causative gene for SDS is the Shwachman-Bodian-Diamond syndrome (SBDS) gene; however, the function of SBDS and pathogenesis of each condition in SDS are largely unknown. SBDS is known to be localized at mitotic spindles and stabilizes microtubules. Previously, we demonstrated that SBDS is ubiquitinated and subsequently degraded in the mitotic phase, thereby accelerating mitotic progression. In this study, we examined mitosis in a myeloid cell model of SDS (SDS cells). 4',6-Diamidino-2-phenylindole (DAPI)-stained chromosome observation and cell cycle analysis of nocodazole-synchronized cells revealed that the SDS cells have abnormally rapid mitosis. In addition, many lagging chromosomes and micronuclei were detected. Moreover, the phosphorylation of threonine tyrosine kinase, the crucial kinase of the spindle assembly checkpoint (SAC), was suppressed. Chromosomal instability caused by SAC dysfunction may cause a variety of clinical conditions, including hematologic tumors in patients with SDS.