Basic and Translational Myology Laboratory, Université Paris Cité, BFA, UMR 8251, CNRS, F-75013 Paris, France.
APHP-Sorbonne Université, Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire, Service de Biochimie Métabolique, HU Pitié Salpêtrière-Charles Foix, F-75013 Paris, France.
Cells. 2023 Jan 16;12(2):337. doi: 10.3390/cells12020337.
A single missense variant of the /LAP2α gene, encoding LAP2 proteins, has been associated with cardiomyopathy in two brothers. To further evaluate its role in cardiac muscle, we included in our cardiomyopathy diagnostic gene panel. A screening of ~5000 patients revealed three novel rare heterozygous variants in six males diagnosed with hypertrophic or dilated cardiomypathy. We identified in different cellular models that (1) the frameshift variant LAP2α p.(Gly395Glufs*11) induced haploinsufficiency, impeding cell proliferation and/or producing a truncated protein mislocalized in the cytoplasm; (2) the C-ter missense variant LAP2α p.(Ala240Thr) led to a reduced proximity events between LAP2α and the nucleosome binding protein HMGN5; and (3) the LEM-domain missense variant p.(Leu124Phe) decreased both associations of LAP2α/β with the chromatin-associated protein BAF and inhibition of the E2F1 transcription factor activity which is known to be dependent on Rb, partner of LAP2α. Additionally, the LAP2α expression was lower in the left ventricles of male mice compared to females. In conclusion, our study reveals distinct altered properties of LAP2 induced by these /LAP2 variants, leading to altered cell proliferation, chromatin structure or gene expression-regulation pathways, and suggests a potential sex-dependent role of LAP2 in myocardial function and disease.
单个错义变体的 /LAP2α 基因，编码 LAP2 蛋白，与两兄弟的心肌病有关。为了进一步评估其在心肌中的作用，我们将其纳入了我们的心肌病诊断基因面板。对~5000 名患者进行筛查后，在 6 名被诊断为肥厚性或扩张性心肌病的男性中发现了三种新的罕见杂合 变体。我们在不同的细胞模型中发现：（1）移码变体 LAP2α p.（Gly395Glufs*11）导致单倍不足，阻碍细胞增殖和/或产生错误定位于细胞质的截断蛋白；（2）C 端错义变体 LAP2α p.（Ala240Thr）导致 LAP2α 与核小体结合蛋白 HMGN5 之间的接近事件减少；（3）LEM 结构域错义变体 p.（Leu124Phe）降低了 LAP2α/β 与染色质相关蛋白 BAF 的结合，并抑制了 E2F1 转录因子的活性，E2F1 转录因子的活性已知依赖于 Rb，LAP2α 的伴侣。此外，与女性相比，雄性小鼠左心室中的 LAP2α 表达水平较低。总之，我们的研究揭示了这些 /LAP2 变体引起的 LAP2 不同的改变特性，导致细胞增殖、染色质结构或基因表达调控途径发生改变，并提示 LAP2 在心肌功能和疾病中存在潜在的性别依赖性作用。
