講演情報
[O26-3]IMAGE-I症候群における新規POLE遺伝子変異の同定とその病態解析
○中野 智太, 笹原 洋二, 菊池 敦生, 森谷 邦彦, 新妻 秀剛, 呉 繁夫 (東北大学 医学系研究科 小児病態学分野)
DNA replisome is a molecular complex that plays an indispensable role in normal DNA replication. IMAGE-I syndrome is one of the DNA replisome-associated genetic diseases caused by biallelic mutations in the DNA polymerase epsilon catalytic subunit 1 (POLE) gene. We characterized clinical manifestations in two patients with IMAGE-I syndrome. Both patients presented growth retardation, adrenal insufficiency, immunodeficiency, and complicated diffuse large B cell lymphoma. We performed whole-exome sequencing and identified three novel POLE mutations: one was a deep intronic mutation, c.1226+234G＞A, common in both patients, and the others were missense (c.2593T＞G) and in-frame deletion (c.711_713del) mutations in each patient. The unique deep intronic mutation produced aberrantly spliced mRNA, and the other mutants showed severely diminished nuclear localization and were rescued by proteasome inhibitor treatment. Functional analysis revealed impaired cell cycle progression and increased phospho-H2A histone family member X expression in both patients. These findings provide a new insight into the mechanism that POLE mutants are highly susceptible to proteasome-dependent degradation in the nucleus resulting in impaired DNA replication and cell cycle progression, characteristic in DNA replisome-associated diseases.