Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006-Oviedo, Spain.
Biochem Soc Trans. 2011 Dec;39(6):1710-4. doi: 10.1042/BST20110677.
Progeroid laminopathies are accelerated aging syndromes caused by defects in nuclear envelope proteins. Accordingly, mutations in the LMNA gene and functionally related genes have been described to cause HGPS (Hutchinson-Gilford progeria syndrome), MAD (mandibuloacral dysplasia) or RD (restrictive dermopathy). Functional studies with animal and cellular models of these syndromes have facilitated the identification of the molecular alterations and regulatory pathways involved in progeria development. We have recently described a novel regulatory pathway involving miR-29 and p53 tumour suppressor which has provided valuable information on the molecular components orchestrating the response to nuclear damage stress. Furthermore, by using progeroid mice deficient in ZMPSTE24 (zinc metalloprotease STE24 homologue) involved in lamin A maturation, we have demonstrated that, besides these abnormal cellular responses to stress, dysregulation of the somatotropic axis is responsible for some of the alterations associated with progeria. Consistent with these observations, pharmacological restoration of the somatotroph axis in these mice delays the onset of their progeroid features, significantly extending their lifespan and supporting the importance of systemic alterations in progeria progression. Finally, we have very recently identified a novel progeroid syndrome with distinctive features from HGPS and MAD, which we have designated NGPS (Néstor-Guillermo progeria syndrome) (OMIM #614008). This disorder is caused by a mutation in BANF1, a gene encoding a protein with essential functions in the assembly of the nuclear envelope, further illustrating the importance of the nuclear lamina integrity for human health and providing additional support to the study of progeroid syndromes as a valuable source of information on human aging.
早衰性层粘连蛋白病是由核包膜蛋白缺陷引起的加速衰老综合征。因此，已经描述了 LMNA 基因和功能相关基因的突变会导致 HGPS（早老性皮肤松弛症）、MAD（下颌面骨发育不良）或 RD（限制性皮肤营养不良）。这些综合征的动物和细胞模型的功能研究促进了参与早衰发展的分子改变和调控途径的鉴定。我们最近描述了一个涉及 miR-29 和 p53 肿瘤抑制因子的新调控途径，这为协调核损伤应激反应的分子成分提供了有价值的信息。此外，通过使用 ZMPSTE24 缺陷的早衰小鼠（涉及层粘连蛋白 A 成熟的锌金属蛋白酶 STE24 同源物），我们已经证明，除了这些异常的细胞应激反应外，生长激素轴的失调是导致与早衰相关的一些改变的原因。这些观察结果一致表明，在这些小鼠中恢复生长激素轴的药理学作用可延迟其早衰特征的发生，显著延长其寿命，并支持系统性改变在早衰进展中的重要性。最后，我们最近非常确定了一种与 HGPS 和 MAD 具有不同特征的新型早衰综合征，我们将其命名为 NGPS（Néstor-Guillermo 早衰综合征）（OMIM#614008）。该疾病是由 BANF1 基因突变引起的，BANF1 基因编码一种在核包膜组装中具有重要功能的蛋白质，这进一步说明了核层粘连蛋白完整性对人类健康的重要性，并为早衰综合征的研究提供了额外的支持，为人类衰老的信息提供了有价值的信息来源。
