Hegele Robert A, Oshima Junko
Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute, London, Ontario, Canada N6A 5K8.
Exp Cell Res. 2007 Jun 10;313(10):2134-43. doi: 10.1016/j.yexcr.2007.03.023. Epub 2007 Mar 30.
Systematic correlation of phenotype with genotype is a key goal of the emerging field of phenomics, which is expected to help define complex diseases. Careful evaluation of phenotype-genotype associations in monogenic disorders, such as laminopathies, might provide new hypotheses to be tested with molecular and cellular studies and might also suggest potential new intervention strategies. For instance, evaluation of the clinical features of carriers of mutant LMNA in kindreds with familial partial lipodystrophy suggests rational, staged intervention using established pharmaceutical agents to prevent cardiovascular complications not just for patients with lipodystrophy but by extension for patients with the common metabolic syndrome. Careful non-invasive imaging shows phenotypic differences between partial lipodystrophy due to mutant LMNA and not due to mutant LMNA. Furthermore, hierarchical cluster analysis detects systematic relationships between organ involvement in laminopathies and mutation position in the LMNA genomic sequence. However, sometimes the same LMNA mutation can underlie markedly different clinical phenotypes; cellular and molecular experiments can help to explain the mechanistic basis for such differences. Finally, promising novel treatment modalities for laminopathies, such as farnesyl transferase inhibition and gene-based therapies, might help not only to illuminate mechanisms that link genotype to phenotype, but also to provide hope for patients suffering with laminopathies, since these treatments are designed to modulate key early or proximal steps in the pathogenesis of these disorders.
将表型与基因型进行系统关联是新兴的表型组学领域的一个关键目标，有望助力明确复杂疾病。仔细评估单基因疾病（如核纤层蛋白病）中的表型 - 基因型关联，可能会为分子和细胞研究提供有待检验的新假说，也可能会提示潜在的新干预策略。例如，对患有家族性部分脂肪营养不良的家族中携带突变型LMNA的个体的临床特征进行评估，表明使用已有的药物进行合理、分阶段干预，不仅可以预防脂肪营养不良患者的心血管并发症，而且通过推广，还可以预防常见代谢综合征患者的心血管并发症。仔细进行的非侵入性成像显示，由突变型LMNA导致的部分脂肪营养不良与非由突变型LMNA导致的部分脂肪营养不良之间存在表型差异。此外，层次聚类分析检测到核纤层蛋白病中器官受累情况与LMNA基因组序列中的突变位置之间存在系统关系。然而，有时相同的LMNA突变可能是明显不同临床表型的基础；细胞和分子实验有助于解释这种差异的机制基础。最后，对于核纤层蛋白病有前景的新型治疗方式（如法尼基转移酶抑制和基于基因的疗法），可能不仅有助于阐明将基因型与表型联系起来的机制，而且还能为患有核纤层蛋白病的患者带来希望，因为这些治疗旨在调节这些疾病发病机制中的关键早期或近端步骤。
